The Ccr4a (CNOT6) and Ccr4b (CNOT6L) deadenylase subunits of the human Ccr4-Not complex contribute to the prevention of cell death and senescence.
The Ccr4a (CNOT6) and Ccr4b (CNOT6L) deadenylase subunits of the human Ccr4-Not complex contribute to the prevention of cell death and senescence.
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DOI：
10.1091/mbc.e10-11-0898
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发表时间：
2011-03-15
影响因子：
3.3
通讯作者：
Winkler GS
中科院分区：
文献类型：
--
作者：
Mittal S;Aslam A;Doidge R;Medica R;Winkler GS
人类Ccr4-Not复合体有两种类型的去烯基酶亚基，它们缩短细胞质mRNA的聚腺苷酸尾部。作者提出了高度相关的Ccr4a/Ccr4b死烯酶在预防细胞死亡和衰老中的新作用的证据，并表明它们与Caf1a/Caf1b死烯酶相比具有不同的作用。胞质mRNA降解的一个关键步骤是poly(A)尾巴的缩短，这涉及到几种死烯酶。对这些酶在细胞生理学中的重要性所知相对较少。在这里，我们重点研究了Ccr4-Not复合物中高度相似的Ccr4a （CNOT6）和Ccr4b （CNOT6L）死基酶亚基的作用。除了在细胞增殖中发挥作用外，Ccr4a和Ccr4b与Caf1a （CNOT7）和Caf1b (CNOT8) deadenylase亚基或Ccr4-Not复合体的CNOT1和CNOT3非催化亚基相比，还在细胞存活中发挥作用。我们发现，Caf1a/Caf1b或Ccr4a/Ccr4b的敲低对加工体组分形成细胞质灶的影响不同，强调了死烯基酶亚基的不同贡献。此外，我们证明Ccr4b的氨基末端富亮氨酸重复（LRR）结构域影响其亚细胞定位，但不是Ccr4b死基化酶活性所必需的。此外，缺乏LRR结构域的Ccr4b过表达干扰细胞周期进程，但不影响细胞活力。最后，基因表达谱分析表明，不同的基因组受到Caf1a/Caf1b和Ccr4a/Ccr4b的调控，并鉴定出Ccr4a/Ccr4b是胰岛素样生长因子结合蛋白5的关键调控因子，该蛋白通过p53依赖途径介导细胞周期阻滞和衰老。
The human Ccr4-Not complex has two types of deadenylase subunits that shorten the polyadenylate tail of cytoplasmic mRNA. The authors present evidence for novel roles of the highly related Ccr4a/Ccr4b deadenylases in preventing cell death and senescence and show that they have distinct roles as compared with the Caf1a/Caf1b deadenylases. A key step in cytoplasmic mRNA degradation is the shortening of the poly(A) tail, which involves several deadenylase enzymes. Relatively little is known about the importance of these enzymes for the cellular physiology. Here we focused on the role of the highly similar Ccr4a (CNOT6) and Ccr4b (CNOT6L) deadenylase subunits of the Ccr4–Not complex. In addition to a role in cell proliferation, Ccr4a and Ccr4b play a role in cell survival, in contrast to the Caf1a (CNOT7) and Caf1b (CNOT8) deadenylase subunits or the CNOT1 and CNOT3 noncatalytic subunits of the Ccr4–Not complex. Underscoring the differential contributions of the deadenylase subunits, we found that knockdown of Caf1a/Caf1b or Ccr4a/Ccr4b differentially affects the formation of cytoplasmic foci by processing-body components. Furthermore, we demonstrated that the amino-terminal leucine-rich repeat (LRR) domain of Ccr4b influenced its subcellular localization but was not required for the deadenylase activity of Ccr4b. Moreover, overexpression of Ccr4b lacking the LRR domain interfered with cell cycle progression but not with cell viability. Finally, gene expression profiling indicated that distinct gene sets are regulated by Caf1a/Caf1b and Ccr4a/Ccr4b and identified Ccr4a/Ccr4b as a key regulator of insulin-like growth factor–binding protein 5, which mediates cell cycle arrest and senescence via a p53-dependent pathway.