Fucci Chiara, Resnati Massimo, Riva Elena, Perini Tommaso, Ruggieri Elena, Orfanelli Ugo, Paradiso Francesca, Cremasco Floriana, Raimondi Andrea, Pasqualetto Elena, Nuvolone Mario, Rampoldi Luca, Cenci Simone, Milan Enrico
Age Related Diseases Unit, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy.
Age Related Diseases Unit, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy; University Vita-Salute San Raffaele, 20132 Milan, Italy.
Cell Rep. 2020 Sep 22;32(12):108162. doi: 10.1016/j.celrep.2020.108162.
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.
FAM46C是一种非典型多聚腺苷酸聚合酶，在高达20%的多发性骨髓瘤（MM）患者中发生独特突变，这意味着它具有组织特异性肿瘤抑制功能。在此，我们报告FAM46C选择性地稳定编码内质网（ER）靶向蛋白的mRNA，从而协同增强控制ER蛋白导入、折叠、N-糖基化和运输的蛋白表达，并促进蛋白分泌。这一作用需要与ER膜驻留蛋白FNDC3A和FNDC3B相互作用。在MM细胞中，FAM46C的表达使分泌能力超过可持续水平，诱导活性氧（ROS）积累、ATP短缺和细胞死亡。FAM46C的活性通过快速蛋白酶体降解或与自噬受体p62的ZZ结构域的抑制性相互作用来调节，后者通过隔离在p62聚集体中阻碍其与FNDC3蛋白的结合。总之，我们的数据揭示了一个协调可持续分泌活性和生存的p62/FAM46C/FNDC3回路，为FAM46C的MM特异性肿瘤抑制作用提供了解释，并揭示了潜在的抗癌治疗机会。
