The E3 ubiquitin ligase and RNA-binding protein ZNF598 orchestrates ribosome quality control of premature polyadenylated mRNAs
The E3 ubiquitin ligase and RNA-binding protein ZNF598 orchestrates ribosome quality control of premature polyadenylated mRNAs
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DOI：
10.1038/ncomms16056
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发表时间：
2017-07-07
影响因子：
16.6
通讯作者：
Sonenberg, Nahum
中科院分区：
文献类型：
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作者：
Garzia, Aitor;Jafarnejad, Seyed Mehdi;Sonenberg, Nahum
编码序列（CDS）内的隐蔽聚腺苷酸化触发核糖体相关质量控制（RQC），随后降解异常mRNA和多肽，核糖体解体和再循环。虽然核糖体亚基解离和新生肽降解是众所周知的，异常mRNA的分子传感器及其作用机制仍然未知。我们使用PAR-CLIP研究了锌指蛋白598（ZNF 598），并发现它与tRNA，mRNA和rRNA交联，从而将蛋白质置于翻译核糖体上。源自AAA解码tRNALys（UUU）的交联读段在其细胞丰度上富集10倍，并且由聚（AAA）编码的聚赖氨酸以ZNF 598依赖性方式诱导RQC。ZNF 598与翻译的polyA片段的相遇触发了几种核糖体蛋白的泛素化，需要E2泛素连接酶UBE 2D 3启动RQC。考虑到人CDS缺乏>4个连续的AAA密码子，通过专门的RNA结合蛋白感测过早放置的polyA尾是RQC的新的基于核酸的监视机制。
Cryptic polyadenylation within coding sequences (CDS) triggers ribosome-associated quality control (RQC), followed by degradation of the aberrant mRNA and polypeptide, ribosome disassembly and recycling. Although ribosomal subunit dissociation and nascent peptide degradation are well-understood, the molecular sensors of aberrant mRNAs and their mechanism of action remain unknown. We studied the Zinc Finger Protein 598 (ZNF598) using PAR-CLIP and revealed that it cross-links to tRNAs, mRNAs and rRNAs, thereby placing the protein on translating ribosomes. Cross-linked reads originating from AAA-decoding tRNALys(UUU) were 10-fold enriched over its cellular abundance, and poly-lysine encoded by poly(AAA) induced RQC in a ZNF598-dependent manner. Encounter with translated polyA segments by ZNF598 triggered ubiquitination of several ribosomal proteins, requiring the E2 ubiquitin ligase UBE2D3 to initiate RQC. Considering that human CDS are devoid of >4 consecutive AAA codons, sensing of prematurely placed polyA tails by a specialized RNA-binding protein is a novel nucleic-acid-based surveillance mechanism of RQC.