Lecture 12

Question 1

How does hepatitis C inhibit IFN response

Answer 1

It encodes NS3-4A a protease which cuts off the cardif or Trif domains.
This makes it so that the cell can not complete the signaling pathway which would have resulted in the production of IRF.

Question 2

Viral Mechanisms for disrupting IFN signaling - Poxvirus

Answer 2

Poxvirus encodes type 1 IFN decoys receptors which are secreted from virally infected cells. These receptors (B18R) are like a sponge in a sense that they bind type 1 IFN preventing them from interacting with the receptors of neighboring cells
- essentially it removes the ligand from the JAK STAT signaling pathway

Question 3

Viral Mechanisms for disrupting IFN signaling - Polyomavirus

Answer 3

• Polyomavirus large T antigen binds to and inactivates JAK1
  ○ Thus the interferon can bind the receptor, but the JAKs cant phosphorylate thus no transcription factor

Question 4

Vaccinia virus (a poxvirus) for IFN signalling does what?

Answer 4

Uses VH1 protein which is a phosphatase that removes the phosphate from the activated STAT1

(is a viral mechanism for disrupting IFN signaling)

Question 5

What does Hepatitis C do that we discussed?

Answer 5

Makes the protein NS5A which blocks the formation of the ISGF3 and STAT dimers
(Viral Mechanisms for disrupting IFN signaling)

Question 6

What activates PKR

Answer 6

dsRNA

Question 7

What is PKR

Answer 7

PKR = an interferon stimulated protein which contributes to the antiviral state

Question 8

What does activated PKR do?

Answer 8

Active PKR leads to a shutdown in protein synthesis by the cell, which can lead to cell death (apoptosis) thus preventing the production of new viruses

Question 9

Steps of PKR mechanism (easy)

Answer 9

1) Portion of PKR’s N terminus can bind dsRNA
2) Self phosphorylates, dimerizes
3) Targets EIF2a, phosphorylates causing transcription to stop

Question 10

What are some ways viruses interfere with PKR?

Answer 10

• Inhibiting dsRNA analog
• Sequestering dsRNA
• Making a competitive inhibitor of dsRNA binding
• Disrupting dimerization
• Blocking PKR-substrate interaction
• Degrading PKR

Question 11

What is OAS and what does it do?

Answer 11

OAS is a 2’-5’-oligoadenylate synthetase that upon activation by dsRNA catalyzes the synthesis of oligomers of adenylic acid

Question 12

What activates RNaseL

Answer 12

oligomers made by activated OAS

Question 13

What does RNaseL do

Answer 13

degrades viral and cellular mRNAs

Question 14

What is the result of OAS and RNaseL

Answer 14

The result is an inhibition and cellular protein synthesis and induction of apoptosis

Question 15

What do Sendai virus C proteins and Simina virus 5 Protein V do?

Answer 15

Block STAT phosphorylation and degrade STAT1, both of which disrupt IFN signaling