内质网
抑制器
分泌物
细胞生物学
化学
内质网相关蛋白降解
未折叠蛋白反应
分泌蛋白
生物化学
生物
基因
作者
Chiara Fucci,Massimo Resnati,E. Riva,Tommaso Perini,Elena Ruggieri,Ugo Orfanelli,Francesca Paradiso,Floriana Cremasco,Andrea Raimondi,Elena Pasqualetto,Mario Nuvolone,Luca Rampoldi,Simone Cenci,Enrico Milan
出处
期刊:Cell Reports
[Elsevier]
日期:2020-09-01
卷期号:32 (12): 108162-108162
被引量:21
标识
DOI:10.1016/j.celrep.2020.108162
摘要
FAM46C is a non-canonical poly(A) polymerase uniquely mutated in up to 20% of multiple myeloma (MM) patients, implying a tissue-specific tumor suppressor function. Here, we report that FAM46C selectively stabilizes mRNAs encoding endoplasmic reticulum (ER)-targeted proteins, thereby concertedly enhancing the expression of proteins that control ER protein import, folding, N-glycosylation, and trafficking and boosting protein secretion. This role requires the interaction with the ER membrane resident proteins FNDC3A and FNDC3B. In MM cells, FAM46C expression raises secretory capacity beyond sustainability, inducing ROS accumulation, ATP shortage, and cell death. FAM46C activity is regulated through rapid proteasomal degradation or the inhibitory interaction with the ZZ domain of the autophagic receptor p62 that hinders its association with FNDC3 proteins via sequestration in p62+ aggregates. Altogether, our data disclose a p62/FAM46C/FNDC3 circuit coordinating sustainable secretory activity and survival, providing an explanation for the MM-specific oncosuppressive role of FAM46C and uncovering potential therapeutic opportunities against cancer.
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