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FAM46C and FNDC3A Are Multiple Myeloma Tumor Suppressors That Act in Concert to Impair Clearing of Protein Aggregates and Autophagy

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FAM46C and FNDC3A Are Multiple Myeloma Tumor Suppressors That Act in Concert to Impair Clearing of Protein Aggregates and Autophagy Author Manuscript Published OnlineFirst on September 22, 2020; DOI: 10.1158/0008-5472.CAN-20-1357 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. FAM46C and FNDC3A are multiple myeloma tumor suppressors that act in concert to impair clearing of protein aggregates and autophagy Nicola Manfrini1,2,*, Marilena Mancino1,3,*, Annarita Miluzio1, Stefania Oliveto1,2, Matteo Balestra1, Piera Calamita1,2, Roberta Alfieri1,#, Riccardo L. Rossi1, Marco Sassoè-Pognetto4, Chiara Salio5, Alessandro Cuomo6, Tiziana Bonaldi6, Marcello Manfredi7,8,9 , Emilio Marengo7,8,10, Elia Ranzato10, Simona Martinotti10, Davide Cittaro11, Giovanni Tonon11,12 and Stefano Biffo1,2. 1 INGM, National Institute of Molecular Genetics, “Fondazione Romeo ed Enrica Invernizzi”, Milan, Italy. 2 Dept. of Biological Sciences, University of Milan, Milan, Italy. 3 Dept. of Clinical Sciences and Community, University of Milan, Milan, Italy 4 Dept. of Neuroscience “Rita Levi Montalcini”, University of Turin, C.so Massimo d’Azeglio 52, 10126 Torino, Italy 5 Dept. of Veterinary Sciences, University of Turin, Largo Paolo Braccini 2, 10095 Grugliasco (To), Italy 6 Dept. of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy 7 Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, Corso Trieste 15, 28100 Novara, Italy; 8 ISALIT, Via Canobio 4/6, 28100 Novara, Italy; 9 Dept. of Translation Medicine, University of Piemonte Orientale, 28100 Novara, Italy; 10 Dept. of Sciences and Technological Innovation, University of Piemonte Orientale, Viale T. Michel 11, 15121 Alessandria, Italy; 11 Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. 12 Functional Genomics of Cancer Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. # Current address: IGM- Institute of Molecular Genetics – CNR, Pavia, Italy. * The two authors contributed equally to the work. Running title: Role of the FAM46C/FNDC3A complex in multiple myeloma. Keywords: UPR, proteasome, FNDC3A, lysosome, secretion. Additional information: This paper was supported by grant AIRC IG 19973 to SB, by grant AIRC 9965 5 ‰ to GT and by unrestricted grant from “Fondazione Romeo ed Enrica Invernizzi”. Correspondence: Stefano Biffo, INGM National Institute of Molecular Genetics, “Fondazione Romeo ed Enrica Invernizzi”, Via Francesco Sforza 35, 20122 Milano, Italy. Tel: +390200660304; Email: [email protected]; [email protected] Competing interests: The authors declare no competing interests. Number of words in main text: 7607, figures: 7. 1 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 22, 2020; DOI: 10.1158/0008-5472.CAN-20-1357 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Multiple myeloma (MM) is a plasma cell neoplasm characterized by the production of unfolded immunoglobulins which cause endoplasmic reticulum (ER) stress and sensitivity to proteasome inhibition. The genomic landscape of MM is characterized by the loss of several genes rarely mutated in other cancers that may underline specific weaknesses of MM cells. One of these is FAM46C that is lost in more than 10% of MM patients. We show here that FAM46C is part of a new complex containing the ER-associated protein FNDC3A which regulates trafficking and secretion and, by impairing autophagy, exacerbates proteostatic stress. Reconstitution of FAM46C in MM cells that had lost it induced apoptosis and ER stress. Apoptosis was preceded by an increase of intracellular aggregates, which was not linked to increased translation of IgG mRNA but rather to impairment of autophagy. Biochemical analysis showed that FAM46C requires interaction with ER-bound protein FNDC3A in order to reside in the cytoplasmic side of the ER. FNDC3A was lost in some MM cell lines. Importantly, depletion of FNDC3A increased the fitness of FAM46C-expressing cells, and expression of FNDC3A in cells that had lost it recapitulated the effects of FAM46C, inducing aggregates and apoptosis. FAM46C and FNDC3A formed a complex that modulates secretion routes, increasing lysosome exocytosis. The cellular landscape generated by FAM46C/FNDC3A expression predicted sensitivity to sphingosine kinase inhibition. These results suggest that MM cells remodel their trafficking machinery to cope with ER stress. Significance This study identifies a new multiple myeloma-specific tumor suppressor complex that regulates autophagy and unconventional secretion, highlighting the sensitivity of multiple myeloma cells to the accumulation of protein aggregates. 2 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 22, 2020; DOI: 10.1158/0008-5472.CAN-20-1357 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction Multiple Myeloma (MM), the second most common hematologic malignancy, is caused by the accumulation of abnormal plasma cells. MM cells retain the plasma cell capability to synthesize and secrete immunoglobulins (Ig)s (1). Ig mRNAs are translated by endoplasmic reticulum (ER) resident ribosomes and undergo conventional secretion. Nascent Ig chains translocate to the ER lumen where they are folded. During this process, fractions of immunoglobulins remain unfolded. The accumulation of unfolded proteins triggers the unfolded protein response (UPR), a three-branch mechanisms which maintains ER homeostasis (2). As part of the UPR process, unfolded proteins are retro-translocated from the ER to the cytoplasm and degraded by the proteasome (3). Indeed, proteasome inhibitors are highly effective for MM treatment (4,5), before clinically resistance develops (6). Accumulation of cytoplasmic proteins that escape proteasome digestion can trigger the formation of intracellular aggregates, aka aggresomes. Aggresomes can be degraded by autophagy, an intricated pathway of cellular events that results in the clearing of doubled- membrane vesicles by the lysosomal degradative pathway. Nowadays, most studies converge on the concept that autophagy and the ubiquitin-proteasome system are integrated (7) and cooperate to clear ubiquitinylated targets. In addition, autophagy-relevant proteins possess activities that intervene on cellular functions linked to membrane biology, such as endocytosis, intracellular vesicular trafficking and conventional and non-conventional secretion (8). Genetic analysis has shown that MM cells have frequent loss of function mutations in genes that are rarely mutated in other cancers (9-11). One of these genes is FAM46C that is mutated in more than 10% of patients of MM (9-11). FAM46C induces apoptosis in MM cell lines (12). FAM46C is a member of a gene family composed of four highly similar proteins, FAM46A, FAM46B, FAM46C, and FAM46D. With the exception of FAM46D, which is lost in 3% of gastric 3 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 22, 2020; DOI: 10.1158/0008-5472.CAN-20-1357 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. cancer patients (13), no mutations of other FAM46 family members have been observed in cancer. Understanding the reason that underlies the specific loss of FAM46C in MM, may open the avenue for specific therapies. Unbiased high throughput screening picked up FAM46C as an interferon-regulated modulator of viral production. In some cases, FAM46C overexpression mildly increased viral production, as for yellow fever virus, or had no effect, as with hepatic HCV (14). In other cases, FAM46C strongly inhibited viral propagation, as in the case of the influenza virus H1N1 (15). These observations suggest that the proviral or antiviral effect of FAM46C may depend from specific differences in the way viral particles are replicated and egressed, rather than from a common process. In this context, autophagy modulation plays important roles in viral intracellular amplification (16). An early in silico analysis predicted that FAM46 proteins constituted a non-canonical terminal transferase (NT) family containing PAP/OAS1 SBD domains (17). Structural resolution of FAM46B, a FAM46C paralog, did not confirm the existence of PAP/OAS1 domains (18) and suggested structural homology to bacterial nucleotidyl transferases. Interestingly, motif analysis of FAM46B scores the presence of VHS (19), GAT (20) and GAE domains. These domains regulate trafficking pathways for cargo retrieval and degradation (21). In short, structural studies suggest that FAM46 family members may also interact with the trafficking machinery. The NT activity of FAM46C was reported to add short A-tails to the 3’UTR of ER-bound mRNAs encoding for immunoglobulins (22,23). These data favored the model that FAM46C increases mRNA stability and translation of immunoglobulin(s) mRNA at the ER, increasing IgG secretion (22-24). These studies, largely based on the comparison of wt FAM46C to mock controls, did not show whether all ER-bound mRNAs increased their translational efficiency, and left the 4 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2020 American Association for Cancer
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