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

Cell Rep. 2020 Sep 22;32(12):108162. doi: 10.1016/j.celrep.2020.108162.

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.

Keywords: FAM46C; FNDC3B; antibody; autophagy; bortezomib; endoplasmic reticulum; multiple myeloma; p62/SQSTM1; plasma cell; secretion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / drug effects
  • Cell Line, Tumor
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism
  • Female
  • Fibronectins / metabolism*
  • Gene Silencing / drug effects
  • Homeostasis* / drug effects
  • Humans
  • Immunoglobulins / metabolism
  • Intracellular Membranes / metabolism
  • Male
  • Mice, Inbred C57BL
  • Multiple Myeloma / pathology
  • Nucleotidyltransferases / metabolism*
  • Plasma Cells / drug effects
  • Plasma Cells / metabolism
  • Positive Regulatory Domain I-Binding Factor 1 / metabolism
  • Proteasome Inhibitors / pharmacology
  • Protein Aggregates / drug effects
  • Protein Binding / drug effects
  • Protein Domains
  • Proteostasis* / drug effects
  • Sequestosome-1 Protein / chemistry
  • Sequestosome-1 Protein / metabolism*
  • Tumor Suppressor Proteins / metabolism*

Substances

  • FNDC3A protein, human
  • Fibronectins
  • Immunoglobulins
  • Proteasome Inhibitors
  • Protein Aggregates
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Tumor Suppressor Proteins
  • PRDM1 protein, human
  • Positive Regulatory Domain I-Binding Factor 1
  • Nucleotidyltransferases
  • TENT5C protein, human