Protein kinase R contributes to immunity against specific viruses by regulating interferon mRNA integrity.
Cytosolic viral RNA recognition by the helicases RIG-I and MDA5 is considered the major pathway for IFN-alpha/beta induction in response to RNA viruses. However, other cytoplasmic RNA sensors, including the double-stranded RNA-binding protein kinase R (PKR), have been implicated in IFN-alpha/beta production, although their relative contribution and mechanism have been unclear. Using cells expressing nonfunctional PKR or reduced levels of kinase, we show that PKR is required for production of IFN-alpha/beta proteins in response to a subset of RNA viruses including encephalomyocarditis, Theiler's murine encephalomyelitis, and Semliki Forest virus, but not influenza or Sendai virus. Surprisingly, although IFN-alpha/beta mRNA induction is largely normal in PKR-deficient cells, much of that mRNA lacks the poly(A) tail, indicating that its integrity is compromised. Our results suggest that PKR plays a nonredundant role in IFN-alpha/beta production in response to some but not all viruses, in part by regulating IFN-alpha/beta mRNA stability.
Schulz
Oliver
O
Immunobiology Laboratory, Cancer Research UK, London Research Institute, London WC2A 3PX, UK.
Pichlmair
Andreas
A
Rehwinkel
Jan
J
Rogers
Neil C
NC
Scheuner
Donalyn
D
Kato
Hiroki
H
Takeuchi
Osamu
O
Akira
Shizuo
S
Kaufman
Randal J
RJ
Reis e Sousa
Caetano
C
D000818:Animals; D004686:Encephalomyocarditis virus / Q000276:immunology*; D016898:Interferon-alpha / Q000096:biosynthesis*; D016899:Interferon-beta / Q000096:biosynthesis*; D051379:Mice; D018345:Mice, Knockout; D009975:Orthomyxoviridae / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism*; D012672:Semliki forest virus / Q000276:immunology*; D029082:Sendai virus / Q000276:immunology; D017945:Theilovirus / Q000276:immunology*; D019892:eIF-2 Kinase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D016898:Interferon-alpha; D012333:RNA, Messenger; D016899:Interferon-beta; D019892:eIF-2 Kinase