Stress-Induced Phosphorylation of PACT Reduces Its Interaction with TRBP and Leads to PKR Activation

详细信息    查看全文

• 作者：Madhurima Singh ; David Castillo ; Chandrashekhar V. Patel ; Rekha C. Patel
• 刊名：Biochemistry
• 出版年：2011
• 出版时间：May 31, 2011
• 年：2011
• 卷：50
• 期：21
• 页码：4550-4560
• 全文大小：977K
• 年卷期：v.50,no.21(May 31, 2011)
• ISSN：1520-4995

文摘

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鈥檚 association with PKR leading to PKR activation. PKR activation by PACT leads to phosphorylation of translation initiation factor eIF2伪, 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鈥檚 ability to activate PKR by weakening PACT鈥檚 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.