Regulation of Early Lymphocyte Development via mRNA Decay Catalyzed by the CCR4-NOT Complex.

Taishin Akiyama,Tadashi Yamamoto

doi:10.3389/fimmu.2021.715675

Abstract

Development of lymphocytes is precisely regulated by various mechanisms. In addition to transcriptional rates, post-transcriptional regulation of mRNA abundance contributes to differentiation of lymphocytes. mRNA decay is a post-transcriptional mechanism controlling mRNA abundance. The carbon catabolite repression 4 (CCR4)-negative on TATA-less (NOT) complex controls mRNA longevity by catalyzing mRNA deadenylation, which is the rate-limiting step in the mRNA decay pathway. mRNA decay, regulated by the CCR4-NOT complex, is required for differentiation of pro-B to pre-B cells and V(D)J recombination in pro-B cells. In this process, it is likely that the RNA-binding proteins, ZFP36 ring finger protein like 1 and 2, recruit the CCR4-NOT complex to specific target mRNAs, thereby inducing cell quiescence of pro-B cells. A recent study showed that the CCR4-NOT complex participates in positive selection of thymocytes. Mechanistically, the CCR4-NOT deadenylase complex inhibits abnormal apoptosis by reducing the expression level of mRNAs encoding pro-apoptotic proteins, which are otherwise up-regulated during positive selection. We discuss mechanisms regulating CCR4-NOT complex-dependent mRNA decay in lymphocyte development and selection.

Highlights

These findings suggest that ZFP36L1 or ZFP36L2 recruits the carbon catabolite repression 4 (CCR4)-negative on TATA-less (NOT) complex and leads to degradation of mRNAs encoding cell cycle-promoting genes, thereby regulating cell cycle entry and exit to promote progression of V(D)J recombination
It is likely that RNA decay-dependent regulation of protein concentrations by the CCR4-NOT complex is most effective when cells receive signals initiating production of large numbers of mRNA transcripts, such as during lymphocyte development
It is likely that ZFP36 ring finger protein-like (ZFP36L) family proteins recruit the CCR4-NOT complex to suppress cell-cycle-related genes and DNA damageresponsive genes during early lymphocyte differentiation

Summary

Frontiers in Immunology

Regulation of Early Lymphocyte Development via mRNA Decay Catalyzed by the CCR4-NOT Complex. MRNA decay is a post-transcriptional mechanism controlling mRNA abundance. MRNA decay, regulated by the CCR4-NOT complex, is required for differentiation of pro-B to pre-B cells and V(D)J recombination in pro-B cells. The carbon catabolite repression 4 (CCR4)-negative on TATA-less (NOT) complex controls mRNA longevity by catalyzing mRNA deadenylation, which is the rate-limiting step in the mRNA decay pathway. In this process, it is likely that the RNA-binding proteins, ZFP36 ring finger protein like 1 and 2, recruit the CCR4-NOT complex to specific target mRNAs, thereby inducing cell quiescence of pro-B cells. We discuss mechanisms regulating CCR4-NOT complex-dependent mRNA decay in lymphocyte development and selection

INTRODUCTION

INITIATION OF THE mRNA DECAY PATHWAY BY DEADENYLATION

CONCLUDING REMARKS