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197 Cards in this Set
- Front
- Back
Describe the IFN system
|
Ancient system
Can be found in primitive vertebrates Uses Type 1 IFN (a/B) |
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What does IFN do?
|
**Combat viral infection through cellular resistance
Can also play a role in cell growth, differentiation and immunomodulation |
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What are the 3 types of IFN?
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Type I: IFN-a/B
Type II: IFN-y TYPE III: IFN-delta |
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What is Type I IFN used for?
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Anti-viral IFN
Fight pathogen invasion Also plays a role in tumour dev'p |
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What is Type II IFN for?
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Immunomodulation
|
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What does Type III IFN do?
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Plays almost a redundant role with Type I
|
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Which cells produce Type I IFN?
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All cells: fibroblasts, epithelial cells, leukocytes, macs, pDCs
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What induces the production of type I IFN?
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PAMPs (virus, dsRNA, LPS)
|
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Where is Type I IFN encoded in humans?
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Chr 9 (no introns)
|
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How many genes are in IFN-a? What is the size of the genes?
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More than 15 hu genes
16-27 kDa in size |
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How many genes does IFN-B have? What is the size of the genes?
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1 gene
28-35 kDa |
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What produces Type II IFN?
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Specialized cells: T cells, macs
|
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What induces the production of type II IFN?
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Mitogens
Ag IL-2 |
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Where in the human genome is IFN-y encoded?
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Chr 12
|
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How many genes does IFN-y encode?
What is its size? How many aa is it? |
1 gene, 3 Introns
20-25 kDa 146 aa long |
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What are the effects of type I IFN?
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Antiviral
Cell growth Ptn Synthesis Apoptosis Recruitment of adaptive immunity Ag Presentation |
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What do MxA, 2'-5' OAS and APOBEC all do in type I IFN?
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Directly involved in antiviral activity
|
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What does MxA do?
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Captures viral structural components, traps them around the ER and stops viral assembly
|
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What does 2'-5' OAS do?
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Triggers degradation of viral RNA
|
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What does APOBEC do?
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Anti-retroviral activity
|
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How does type I IFN exercise its antiviral activity?
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Does this through its recpetors
Gets 100s of genes transcribed -->Central mediators of antiviral resistance are transcribed |
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Whatdoes Type I IFN make to control cell growth?
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PKR: main inhibitor of cell growth
If you stop cell growth, viral growth dec |
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What else does PKR affect?
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Ptn synthesis
-> PKR decreases Ptn synthesis |
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What does type I IFN induce to control apoptosis?
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Noxa
TRAIL p53 Caspase 8 These all regulate apoptosis, which is caused by IFN |
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Why is Type I IFN involved in the recruitment of adaptive immunity?
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Increases adaptive immunity when T cell show up, so they can immediately respond to APC
-->MHC I caused by Type I IFN |
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What genes are involved in the recruitment of adaptive immunity?
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RANTES
IP-10 (CXCL10) |
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How is IFN activated?
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IFN regulatory factor (IRF1) binds regulatory element on promoter and causes IFN-secretion
IRF-3 and IRF-7: main inducers of Type I IFN -IRF-3 and 7 are normally inactive in the cell cytoplasms, but when they're P, they become activated, dimerize and go to the nucleus -There, they bind to IFN virus-responsive element (IFVRE) -Kinases that P them belong to the IKK family: IKK-e and TBK-1 |
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Does IKK-e or TBK1 signal through NF-kB?
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No they don't and they don't P IKKs
|
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What do IKK-e and TBK1 recognize?
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C-terminal of IRF-3 and IRF-7
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When do these kinases trigger their P?
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After viral activation
|
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What is the structure of the IFN-B enhancesome?
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ATF-2 -- c-Jun-- IRF3A -- IRF7B--IRF3C -- IRF7D --p53 -- RelA
|
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What is important about the binding sites of IFN-B?
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Binding sites overlap .: all factors must bind co-operatively to DNA (the DNA is mostly linear)
|
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What happens if one of the factors is deleted?
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Cannot make any IFN-B at all
.: Needs to be highly specific and activated all 3 paths (not just NF-kB etc) |
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What is required to get T of IFN-B?
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Recruitment of cofactors
|
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Describe the recruitment of the cofactors
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In the IFN-B locus, there are 2 nucleosomes positioned up and downstream of the enhancesome
Enhancesome is free of nucleosomes and is exposed There is a nucleosome on top of the TATA box that stops T initiation When everything is in place, GCN-5 comes in and adenylates histones in the nucleosome -Enhancement of A of H3 & H4 in nucleosomes and downstream on enhancesome CBP recuited (after GCN-5 leaves) CBP interacts withs IRF, NF-kB and AP-1 When all 3 are recruited, CBP gets a very stable interaction CBP brings Poll II holoenz, SI/SNF complex Histone is unwound and T start site is revealed |
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What are the master regulators of IFN transcription?
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NF-kB
IRFs |
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What is the NF-kB pathway used for?
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Central regulator of cell surviva, proliferation, apoptosis, innate immune response to viruses and bacteria, adaptive immunity
|
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Describe the NF-kB pathway.
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Activation
Signal transduction cascade (variable depending on the type of stimuli) P of IKK so NF-kB can be transduced Degradation of IKK NF-kB dimers can go to the nucleus, recruit regulators -->Get TF --> Expression of many genes (including IK-Balpha) |
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How many gps of Rel/NF-kB TF and IkB family members are there?
What are they? |
3
DNA binding, Non-DNA binding, Inhibitors |
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What are the DNA binding members?
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p65, c-Rel
p52, p50 |
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What are the more important members of the DNA binding gp?
Why? |
p65/c-Rel
They are the activating members Their C-terminal has an activation domain that can recruit CBP |
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What do all the DNA binding members have?
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Rel-homology domain
|
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What is the Rel homology domain important for?
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Required for dimerization and DNA binding
|
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What are p50/p52 important for?
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Important for transactivation when dimerized with an activating member
->They cannot transactivate on their own |
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What do homodimers of p50/p52 act as?
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Inhibitors
|
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How do inhibitors work?
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They bind the Rel homology domains by virtue of their Ankyrin repeats
They inhibit DNA binding ability of the other members and sequester them |
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What is the PEST domain on the inhibitors?
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Sequence that targets ptns for degradation, but they aren't degraded everytime
Need P events for degradation to take place |
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Describe the non-DNA binding gp members
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Hybrid of the DNA binding and inhibitor gps
They have long precursors Have Rel-homology domain and Ankyrin repeats |
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What are the members of the non-DNA binding gp?
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p105 and p100
|
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What's the difference between the p100 and p105?
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p105: precursor for p50
-->It is constitutively cleaved p100: precursor for p52 -->highly regulated, only cleaved under special situations -->Part of the non-canonical NF-kB path |
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What happens when the IKK complex P a ptn?
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Gives the signal for Ub and ptn degradation
|
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Describe the IkBalpha ptn
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Signal domain reponse ---- Ankyrin repeats ---- PEST domain
|
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What is the IkBalpha regulated by?
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At the T level, regulated by NF-kB itself (negative fdbk loop)
|
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What is the PEST domain of IkBa for?
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Important for its degradation
|
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Describe the cycle of IkBa
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NF-kB acitvation makes NF-kB bind to the IkB promoter
When IkB is synthesized, NF-kB is inhibited => Shut off the signal Negative regulator mechanism Keep control of IR |
|
Physiological fcts of NF-kB
What happens to mice with p65KO? |
p65 = DNA binding (activating mb)
If p65 is KO: get massive apoptosis and liver degeneration, mouse dies |
|
Physiological fcts of NF-kB
What happens to mice with RelB KO? |
Rel B also part of DNA binding
RelB expression is restricted to lymphoid tissues. ->RelB -/-dev'l normally until day 10 Then they start expressing thymic atrophy, splenomegaly, hyperplasia and *Dysfunctional immune response* |
|
Physiological fcts of NF-kB
What happens to mice that are c-rel -/-? |
C-rel is restricted to hematopoeitic cells
C-rel -/- have profound lymphocyte activation defects |
|
What is C-rel important for?
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Important mediator downstream of BCR and TCR
|
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What happens to mice with a p50 -/-?
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No developmental abnormalities
BUT --> they have increased susceptibility to bacterial infection AND--> Increased RESISTANCE to viral infection |
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Which members are more important in mediating acute immune responses?
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p50 and C-rel
|
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What are p65 and RelB important for?
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p65: liver development
RelB: development of the hematopoeitic system |
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What are the 3 subunits of IKK complex?
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a, B and y
|
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Are these 3 subunits redundant?
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No, KO each one and you get a different result
|
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What happens if you KO IKKa?
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Mice die at birth with multiple developmental defects
IKKa not required for activation of NF-kB and degradation of IkB by proinflam stimuli (only true for canonical path) |
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What happens to mice that are IKKB -/-?
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Mice progressivle died cuz of liver degeneration and apoptosis (like with p65 -/-)
-Also have reduced basal NF-kB activity and impaired cytokine induced kinase activity |
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What happens to IKKy -/- mice?
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Male IKKy-//- mice died in utero
IKKy -/- female mice developed patchy skin lesions with massive granulocyte infiltration and hyperproliferation and increased apoptosis of keratinocytes |
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Describe the canonical NF-kB path (classical path)
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TACI/BCMA/TNFRa
Signal through TRAF2 which sgnals to the IKK complex (Entire complex) Signals IkBa which complexes with p50 and p65 which go to the nucleus after IkBa is P and goes to the proteasome |
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Describe the non-canonical path (alternative path)
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BAFFR/CD40
(Triggered by different stimuli) Signal through NIK (different kinase, not TRAF) NIK usually unstable, but stabilizes once it binds its ligand and P p100 Processing, than activates p52 and RelB, whicha activate different set of factors |
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Are both these paths completely separate?
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No, there is cross talk betwen the 2 paths
NIK can also activate the classical path |
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What is the role of TRAF3?
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Usually keeps NIK inactive (also can keep TRAF2 inactive)
|
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Why do viruses go after the NF-kB path?
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This path is important for cell surival and growth, increased ptn production
Virus wants to use this |
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How do the following viruses subvert this path?
HIV HTLV EBV |
HIV: Tat ptn can bind IKKy. Also acts through PLC to activate NF-kB
HTLV-1: Tax ptn -> activates NF-kB EBV: activates NF-kbB through non-canonical path |
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What are the IFN regulatory factors (IRFs)?
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Family of TFs
Regulate IFN and IFN-stimulated genes Bind IFN stimulated response element (ISRE) |
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What does IRF-1 do?
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Activator of IFN-B
|
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What does IRF-2 do?
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Inhibitor of IFN-B
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What do IRF 3 and 7 do?
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Main regulators of Type I IFN
|
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What do IRF 1,5,9 do?
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Participate in regulation of Type I IFN, but play different roles
|
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What do IRF 4 and 8 do?
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Involved in lymphoid development
|
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What does IRF 6 do?
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Repressor
|
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What do viral IRFs do?
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Repressor of host IR
|
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What are the key mediators of IFN production?
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IRF 3 and IRF 7
|
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Describe the IRF-3 operon
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DNA binding domain --- PRO --- IAD --- RD
|
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What is the RD?
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Rel homology domain
|
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What does the RD do?
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Allows dimerization
Allows DNA binding and interation btw binding parts |
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What needs to happen to the C-term of the IRF operon (RD)?
Why? |
P
P allows the structure to open up and DBD unmasked by inhibitory domain Highly polar PO4 gps change C-term -Expose hetero/homo dom |
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What does the DBD recognize?
|
ISRE
-Has a NLS that is required for its transloation when its active |
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Describe the IRF-7 operon
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DBD--- CAD --VAD--ID ---RD
|
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What is CAD?
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Constitutive Activation Domain
|
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What is VAD?
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Viral activation domain
|
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What does virus inducible P of IRF 3 at the C terminus regulate?
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Cytoplasmic-nuclear translocation: nuc localization seqwuence will become exposed
Ass't with CBP/p300 co-actiator Trasactivation of virus responsive promoters Proteasome mediated degradation: when signal is done and gene is T, IRF3 will be degraded |
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What form of IRF3 appears after viral infection?
Why? |
Heavier form of IRF3 appears becuase it gets P
|
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Where is IRF3 when its not activated?
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Mainly cytoplasmic, but shuttles in and out of nucleus
|
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Where is IRF 3 after viral activation?
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In the nucleus
|
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Is P of IRF 3 sufiient ot cause IFN-B?
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Yes (IRF3 (5D) )
|
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What does CBP interact with?
|
The 3 helices of the IRF3 AD
(C-term region of IRF3 also interacts with this region) |
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What is the main difference btw IRF 3 and IRF 7 that makes them non-redundant?
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IRF3 expression is constitutive
=>All cells at all ties have IRF-3 expressed in their cytoplasm =>1st factor activated when the virus comes in IRF-7 expression is induced =>You need the 1st wave of IFN production so that the neighboring cells can detect the IFN -->The IRF-7 will be part of the IFN-stimulated gene production -->ITF-7 will then be preset in the cytoplasm =>IRF-3 is part if the initial response and IRF-7 will be part of the secondary response/amplification response |
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What makes more IFN, IRF 3 or IRF 7?
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IRF 7 makes sigificantly more
|
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What does IRF 7 induce?
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Production of IFN-B
|
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What does IRF 3 induce?
|
Only certain types of IFN-a (can induce IFN-a2, but not IFN-a1)
|
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Which cells have constitutive IRF 7 expression?
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Macs and plasmaytoid DCs
|
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Why don't all cells have constitutive IRF 7 expression?
|
IRFs do differet things.
IRF 7 can stumulate all types of type I IFN IRF 3 can only stimulate certain types of type I IFN |
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What kind of an experiment could be designed to show the difference between the type of mac with constitutive expression of IRF 3 or IRF 7?
|
Take amac
Put a constitutively active form of IRF 3 or IRF7 into an adenovirus casette, then put gene in macs so macs can express active form of the IRFs |
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What kind of experiment can be done to see the big differences?
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Use microarrays
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Which genes are shared by both IRF 3 and 7 when you llok at a microarray of it?
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PRR paths (TLR/NF-kB/JAK-STAT)
IFN-stimulated genes (ISF) Chaperones Stress release ptns Ub path |
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What are 2 very different gees btw IRF3 and IRF 7?
|
Apoptotic response
Tumoricidal and immune fct |
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Which IRF can induce apoptosis?
|
IRF3
|
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How does a cell detect infection?
|
Pathogen recognition receptors:
-TLRs -NLRs -DAI: DNA sensors, rec'z DNA in the cytoplasm -RLRs: RIG-I, Mda5 |
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What kind of a structure do the RLRs have?
|
Helical
|
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What do RLRs rec'g?
|
Viral dsRNA (rec'z these using their helical structures)
|
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What do NLRs recognize?
What do they signal through? |
Re'z bact compartments
Signal through inflammasome for NF-kB |
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Where are TLRs mainly expressed?
|
Macs, DCs, monocytes and B cells
-->Regular cells don't express TLRs |
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Describe the TLR structure
|
Ectodomain: sigal peptide, LRR, cystein-rich domain
Transmb domain: single pass Intracellular domain: TIR (toll-IL1 receptor) domain |
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What does the ectodomain do?
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PAMP rec'g and binding
|
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What does the TIR domain do?
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Reruits adaptors
|
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What does TLR3 reognize?
|
ds RNA
|
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What does TLR4 rec'z?
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LPS + other things
|
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What is TLR4 the main mediator of?
|
Septic shock
|
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What does TLR7 rec'z?
|
ssRNA
|
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What does TLR8 rec'z?
|
ssRNA
small synthetic cmpds |
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What does TLR9 rec'g?
|
unmethylated CpG (on bacteria and viral DNA)
|
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Which apoptotic gene does IRF-3 induce greater amounts of than IRF 7?
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NOXA
|
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What is the key place for apoptosis induction?
|
Mitochondria
|
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Where does cyt C have to go for apoptosis?
|
From mito to cytoplasm
|
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How does cyt C escape the mito?
|
Bax/Bak oligomerize
Get pore formation Cyt C can get out |
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How are Bax/Bak usually kept inactive?
|
By binding anti-apoptotic members of the Bcl2 family (MCL-1)
|
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What happens when the cell is stressed?
|
Get NOXA expression
Binds MCL-1 Displaces it from Bax/Bak .: Bax/Bak makes an oligo to form porers to trigger cyt C release -->NOXA aloe a help trigger olig of bax/Bak End result: Cyt C release ad activation of apoptosis .:IRF3 activates NOXA T and thats all it needs |
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What does active IRF-3 expression do to the NOXA promoter?
|
Induces it
|
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What does active IRF7 do to macrophages?
|
Increases their killing ability
->IRF7 doesn't increase apoptosis but increased death of neighboring cells |
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What happens to cells infected with chimeric Adeno-F7?
|
Inhibit prolif of target cells
|
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Is this process completely dependent on IFN?
What does this mean? |
No, because when the chimeric insert is removed, the cell doesn't go back to basal lvl of type I IFN
.: IRF-7 induces very specific types of cells that don't need type I IFN |
|
What kind of genes are involved in active IRF-7 expressig macs?
|
Genes and cytokine genes involved in AP, cross presentation and cell killing
|
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What are the effects or IRF7 activation?
|
Release soluble factors
Inc AP Recruit TH1 by secretion of IFNa/B, IP-10, RANTES Recruit NK cells because of RANTES, IL-15, IL27 Release TRAIL and IFNa/B to kill infected cell |
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What is the distict role of IRF3?
|
In all non-immune cells
Triggers restricted, specific antiviral response Strong pro-apoptotic response mediated by upregulation of NOXA |
|
What is the distinct role of IRF7?
|
In specialized immune cells (pDCs and Macs)
Amplifies antiviral response by induction of multiple type I IFN species ad ISG Stimulates IR fct (inc AP) Inductio of anti-tumour fcts of macs Weak apoptotic response |
|
Describe TLR4 structure
|
Horse shoe structure
|
|
What happens whe a ligand binds its TLR? (usually binds at surface ad not at the groove)
|
Causes olig. in the cytoplasmic part
Brings 2 TIR domains in proximity and this starts the signalling |
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Which cells express all TLRs?
|
DCs
Monocytes/macs |
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What do B cells ad mast cells express?
|
Subset of TLRs
|
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What do T cells express?
|
Some TLRs
|
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Why do airways and intestinal epithelium express a subset of TLRs?
|
Sites of pathogen entry
|
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Do neurons express any TLRs?
|
Yes (TLR 12 and 13, unknown fct)
|
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Describe TLR signalling
|
Mainly through adaptors ad TIR domain
|
|
How many adaptors does TLR 4 have?
|
4adaptors:
MyD88 MAL TRAM TRIF |
|
How many adaptors does TLR 3 have?
|
1: TRIF
|
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How many adaptors does TLR 7/8/9 have?
|
1: MyD88
|
|
What happens once the TLRs signal through the adaptors?
|
Get recruitment of kinases,
Activate IKK and TBK1/IKKe that P the target T factors Get antiviral and inflam response |
|
What is TLR4 signalling always ass't with?
|
MD2 and CD14
|
|
What rec'z LPS that is shed by G- bacteria?
|
LBP (LPS Binding Ptn)
|
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What on the host cell recognizes the LPS-LBP complex?
What does it do? |
CD14
CD14 loads the LPS-LBP complex onto TLR4 and allows its dimerization |
|
What hapens once TLR4 dimerizes?
|
TIR domains come into close contact and there is initiation of signalling cascade
|
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Which adaptors are recruited following TIR domain activation?
|
MAL and MyD88
|
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What is TLR4 signalling always ass't with?
|
MD2 and CD14
|
|
What rec'z LPS that is shed by G- bacteria?
|
LBP (LPS Binding Ptn)
|
|
What on the host cell recognizes the LPS-LBP complex?
What does it do? |
CD14
CD14 loads the LPS-LBP complex onto TLR4 and allows its dimerization |
|
What hapens once TLR4 dimerizes?
|
TIR domains come into close contact and there is initiation of signalling cascade
|
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Which adaptors are recruited following TIR domain activation?
|
MAL and MyD88
|
|
What do the adaptors then recruit? What does it do?
|
IRAK-4, which P TRAF6
|
|
What is TRAF-6?
|
UB-lyase of TAK-1/TAB
|
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What happens once the TAK/TAB complex is Ub?
|
Complex gets activated
MAPK cascade is activated --->Get production of ATF2/c-JUN in the cytoplasm |
|
What happens to TLR4 after this signaling path?
|
TLR4 gets translocated to the endosome
|
|
What does TLR4 recruit once its in the endosome?
|
Recruits TRIF through Adaptor TRAM
|
|
What do TRIF and TRAM cause?
|
Another signalling cascade is initiated through TRADD and RIP1, which also feeds into the TRAF-6/NF-kB path
(This is how you get early and late NF-kB activation) |
|
How is TRAF3 recruited to TRAM?
|
Through endosomal signalling
|
|
What does TRAF3 do?
|
Signals to TBK-1 and IKKe (kinases) to activate IRF 3 and IRF 7
|
|
What does TLR 4 signaling induce?
|
NF-kB signalling
IRF signalling AP-1 activation |
|
What happens when all 3 of these systems are actvated?
|
Get inductionof IFN- genes
|
|
How does the TLR3 signal path go?
|
Similar to TLR 4 signalling
Works through TRIF, recruits TRAF 6 and get IKK/TBK to get IRF3/7 production |
|
Which cells use RIG-I-like receptors?
|
The common cells
|
|
What are the 2 RLRs?
|
RIG-I
Mda5 |
|
What is LGP2?
|
Truncated form of the Mda5 regulator. Acts as an inhibitor
It is not mb bound. Resides in the cytoplasm |
|
What kind of expression do RIGI and Mda5 have?
|
Constitutive expression in all cells
|
|
What induces the RLRs?
|
Type I and II IFN
|
|
Where are the RLRs localized?
|
Cytoplasm
|
|
Describe the Structure of RLRs.
|
2 CARD domains--- DExD/H box helicase ---- CTD/RD
|
|
What does the C-term domain of RLRs recognize? How?
|
dsRNA
Rec'z it through the helicase domain and 2 CARD domains that mediate ptn-ptn interactions and signal transduction |
|
What do the CARD domains of the RLRs interact with?
|
MAVS (adaptor ptn)
|
|
What is MAVS?
|
Main transductor of signalling
-->Adaptor that all signalling components bind to |
|
What is another adaptor molecule that is essential for IFN signalling by RIG-I?
|
IKK-y/NEMO
|
|
What does NEMO do?
|
Interacts with IKKe and TBK-1 through TANK
|
|
Whgat localizes MAVS to the outer mitochondrial mb?
|
TM domain
|
|
What happens once the RLR is activated?
|
CARD-CARD interactions recruit MAVS. which bring in TRAFs
|
|
What does TRAF 3 signal to?
|
IKKe and TBK1
-->Get production of IRF3/7 |
|
What does TRAF6 do?
|
Brings in TK kinasa
-->Get MAPK activation =>ATF-2/c-Jun -->get removal of IKK complex => get NF-kB activation |
|
What happens when TRADD and FAD are recruited?
|
Get activation of Caspases
|
|
What happens during the 2nd wave of IFN signalling?
|
IFN-a binds its receptors, recruits STATs which complex with IRF9
Forms ISGF3 complex Get an antiviral response by activating production of IRF-7 when ISGF3 binds ISRE and also produce more IFN-a |
|
What happens when type I IFN binds its receptors on neigboring cells?
|
Jaks cross-P each othr
Activated Jaks P receptors on tyrs STATs dock and Jaks P them STATs diss't from the receptor and dimerize through SH2 domains Ass't with IRF9 to form the ISGF3 complex ISGF3 complex binds ISRE and get T of ISGs in the nucleus |
|
What kind of STATs are involved in Type I and III signalling?
|
STAT 1 & 2 (forms ISGF3 complex)
Antiviral activity |
|
What STATs does type II IFN actiate?
|
Only STAT-1
-->antimicrobial immunity |
|
What are ISGs?
|
IFN-inducible genes
|
|
What are ISGs for?
|
Antiviral immunity
|
|
What is ISG15 like?
|
Ubiquitin, but plays an antiviral role
|
|
What happens when ISG15 is conjugated to target ptns?
|
Seems to lead to a permanence of IFN response
|
|
Why is MxA an antiviral trap?
|
It is produced as a monomer, but it oligomerizes and traps viral components in the ER
|
|
What does OAS1 do, after being produced by ISRE?
|
The OAS1 monomer is inactive
Active when becomes a tetramer Gets polyadenyulated Activated RNAse L and lets it dimerize |
|
What does RNAse L do after is dimerizes?
|
Chops RNA into small pieces and destroys viral RNA
Generates fragments tht can be rec'z by RLRs and trigger immunity |
|
What does PKR do?
|
Its made as an inactive monomer
Becomes activev in the presence of viral RNA Stops Tl by P of EIF-2a |