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. 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.

Fucci, C., Resnati, M., Riva, E., Perini, T., Ruggieri, E., Orfanelli, U., et al. (2020). The Interaction of the Tumor Suppressor FAM46C with p62 and FNDC3 Proteins Integrates Protein and Secretory Homeostasis. CELL REPORTS, 32(12) [10.1016/j.celrep.2020.108162].

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

Riva E.;
2020

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. 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.
Articolo in rivista - Articolo scientifico
antibody; autophagy; bortezomib; endoplasmic reticulum; FAM46C; FNDC3B; multiple myeloma; p62/SQSTM1; plasma cell; secretion; Animals; Autophagy; Cell Line, Tumor; Endoplasmic Reticulum; Female; Fibronectins; Gene Silencing; Humans; Immunoglobulins; Intracellular Membranes; Male; Mice, Inbred C57BL; Multiple Myeloma; Nucleotidyltransferases; Plasma Cells; Positive Regulatory Domain I-Binding Factor 1; Proteasome Inhibitors; Protein Aggregates; Protein Binding; Protein Domains; Sequestosome-1 Protein; Tumor Suppressor Proteins; Homeostasis; Proteostasis
English
22-set-2020
2020
32
12
108162
none
Fucci, C., Resnati, M., Riva, E., Perini, T., Ruggieri, E., Orfanelli, U., et al. (2020). The Interaction of the Tumor Suppressor FAM46C with p62 and FNDC3 Proteins Integrates Protein and Secretory Homeostasis. CELL REPORTS, 32(12) [10.1016/j.celrep.2020.108162].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/327697
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