Regulation of CCR4-NOT Complex Deadenylase Activity and Cellular Responses by MK2-dependent Phosphorylation of CNOT2

Overview

Journal RNA Biol

Specialty Molecular Biology

Date 2022 Feb 7

PMID 35129087

Authors

Toru Suzuki

Miyuki Hoshina

Saori Nishijima

Naosuke Hoshina

Chisato Kikuguchi

Takumi Tomohiro

Akira Fukao

Toshinobu Fujiwara

Tadashi Yamamoto

Affiliations

Soon will be listed here.

Abstract

CCR4-NOT complex-mediated mRNA deadenylation serves critical functions in multiple biological processes, yet how this activity is regulated is not fully understood. Here, we show that osmotic stress induces MAPKAPK-2 (MK2)-mediated phosphorylation of CNOT2. Programmed cell death is greatly enhanced by osmotic stress in CNOT2-depleted cells, indicating that CNOT2 is responsible for stress resistance of cells. Although wild-type (WT) and non-phosphorylatable CNOT2 mutants reverse this sensitivity, a phosphomimetic form of CNOT2, in which serine at the phosphorylation site is replaced with glutamate, does not have this function. We also show that mRNAs have elongated poly(A) tails in CNOT2-depleted cells and that introduction of CNOT2 WT or a non-phosphorylatable mutant, but not phosphomimetic CNOT2, renders their poly(A) tail lengths comparable to those in control HeLa cells. Consistent with this, the CCR4-NOT complex containing phosphomimetic CNOT2 exhibits less deadenylase activity than that containing CNOT2 WT. These data suggest that CCR4-NOT complex deadenylase activity is regulated by post-translational modification, yielding dynamic control of mRNA deadenylation.

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