An Endoplasmic Reticulum (ER) Stress-Induced Protein Controls a Protein Kinase — Implications for Viral Infections

David Ron
New York University School of Medicine
R01ES08681

Background: Cells react to environmental stressors by regulation of mRNA translation. A key step in this process is modification of the phosphorylation of a protein known as eukaryotic initiation factor (eIF) 2α. In eukaryotic cells, eIF2α kinases have been identified including protein kinase R (PKR), which is activated during cellular responses to the accumulation of unfolded proteins in the ER. Another is PKR-like ER kinase (PERK). In response to viral infection, host cells stimulate PKR-mediated eIF2α phosphorylation, thus shutting off protein synthesis including the synthesis of viral proteins.

Advance: Previous research in this laboratory identified a PKR inhibitor, P58^IPK, which is activated after influenza virus infection. The present study sought to gain insight into additional functions of P58^IPK. Among the findings presented, the investigators report that P58^IPK interacts with and inhibits PERK activity and plays a role in the expression of downstream markers of PERK activity in ER-stress response.

Implication: These studies show that with respect to P58^IPK, the influenza virus has found a way to co-opt a host gene in order for the virus to proliferate in the host cells. Although this is a very basic discovery, it provides insight into the mechanisms by which the influenza virus uses its host's cellular mechanisms to cause infection and illness. This finding may be useful in designing new therapeutic mechanisms to fight infection of influenza viruses.

Citation: Yan W, Frank CL, Korth MJ, Sopher BL, Novoa I, Ron D, Katze MG. Control of PERK eIF2alpha kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK. Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):15920-5.