The Interaction of the Tumor Suppressor FAM46C with p62 and FNDC3 Proteins Integrates Protein and Secretory Homeostasis

Chiara Fucci, Massimo Resnati, Elena Riva, Tommaso Perini, Elena Ruggieri, Ugo Orfanelli, Francesca Paradiso, Floriana Cremasco, Andrea Raimondi, Elena Pasqualetto, Mario Nuvolone, Luca Rampoldi, Simone Cenci, Enrico Milan

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article number108162
JournalCell Reports
Volume32
Issue number12
DOIs
Publication statusPublished - Sep 22 2020

Keywords

  • antibody
  • autophagy
  • bortezomib
  • endoplasmic reticulum
  • FAM46C
  • FNDC3B
  • multiple myeloma
  • p62/SQSTM1
  • plasma cell
  • secretion

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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