Stress-induced phosphorylation of PACT reduces its interaction with TRBP and leads to PKR activation.

Abstract:

:PACT is a stress-modulated activator of interferon (IFN)-induced double-stranded (ds) RNA-activated protein kinase (PKR) and is an important regulator of PKR-dependent signaling pathways. Stress-induced phosphorylation of PACT is essential for PACT's association with PKR leading to PKR activation. PKR activation by PACT leads to phosphorylation of translation initiation factor eIF2α, inhibition of protein synthesis, and apoptosis. In addition to positive regulation by PACT, PKR activity in cells is also negatively regulated by TRBP. In this study, we demonstrate for the first time that stress-induced phosphorylation at serine 287 significantly increases PACT's ability to activate PKR by weakening PACT's interaction with TRBP. A non-phosphorylatable alanine substitution mutant at this position causes enhanced interaction of PACT with TRBP and leads to a loss of PKR activation. Furthermore, TRBP overexpression in cells is unable to block apoptosis induced by a phospho-mimetic, constitutively active PACT mutant. These results demonstrate for the first time that stress-induced PACT phosphorylation functions to free PACT from the inhibitory interaction with TRBP and also to enhance its interaction with PKR.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Singh M,Castillo D,Patel CV,Patel RC

doi

10.1021/bi200104h

subject

Has Abstract

pub_date

2011-05-31 00:00:00

pages

4550-60

issue

21

eissn

0006-2960

issn

1520-4995

journal_volume

50

pub_type

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