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

C. Fucci, M. Resnati, E. Riva, T. Perini, E. Ruggieri, U. Orfanelli, F. Paradiso, F. Cremasco, A. Raimondi, E. Pasqualetto, M. Nuvolone, L. Rampoldi, S. Cenci, E. Milan

Research output: Contribution to journalArticlepeer-review

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. © 2020 The Authors Fucci et al. show that the poly(A) polymerase FAM46C acts as a multiple myeloma-specific tumor suppressor, increasing secretory capacity and antibody production beyond sustainability via its interaction with endoplasmic reticulum transmembrane FNDC3 proteins. Moreover, its activity is restricted through proteasomal degradation or p62-dependent aggregation and sequestration from FNDC3 proteins. © 2020 The Authors
Original languageEnglish
JournalCell Rep.
Volume32
Issue number12
DOIs
Publication statusPublished - 2020

Keywords

  • antibody
  • autophagy
  • bortezomib
  • endoplasmic reticulum
  • FAM46C
  • FNDC3B
  • multiple myeloma
  • p62/SQSTM1
  • plasma cell
  • secretion
  • adenosine triphosphate
  • FAM46C protein
  • FNDC3A protein
  • FNDC3B protein
  • membrane protein
  • messenger RNA
  • reactive oxygen metabolite
  • sequestosome 1
  • tumor suppressor protein
  • unclassified drug
  • animal cell
  • apoptosis
  • Article
  • bioaccumulation
  • controlled study
  • endoplasmic reticulum membrane
  • enzyme activity
  • enzyme regulation
  • female
  • glycosylation
  • human
  • human cell
  • male
  • mouse
  • nonhuman
  • priority journal
  • protein aggregation
  • protein degradation
  • protein expression
  • protein homeostasis
  • protein protein interaction
  • protein RNA binding
  • protein secretion

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