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

Abstract

Multiple myeloma 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 multiple myeloma is characterized by the loss of several genes rarely mutated in other cancers that may underline specific weaknesses of multiple myeloma cells. One of these is FAM46C that is lost in more than 10% of patients with multiple myeloma. 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 multiple myeloma 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 to reside in the cytoplasmic side of the ER. FNDC3A was lost in some multiple myeloma 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 multiple myeloma 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.

Cytoplasmic polyadenylation by TENT5A is required for proper bone formation

“…Accordingly, both TENT5A and TENT5C are clearly associated with membranes (Figure S6B; Bilska et al, 2020). TENT5C association with the ER was also recently confirmed by others, and the mechanism of such association was proposed (Fucci et al, 2020;Manfrini et al, 2020). TENT5 substrates do not harbor any detectable specific sequence motives and represent very abundant mRNAs, suggesting that the mechanism determining substrate specificity relies on localization rather than sequence recognition.…”

Structural and functional characterization of multiple myeloma associated cytoplasmic poly(A) polymerase FAM46C

“…The polyadenylation activity of FAM46C is thought to be essential in this process by influencing the poly(A) tail length, hence the steady‐state levels of the mRNAs of Ig [ 27 , 28 ]. By forming complex with endoplasmic reticulum (ER)‐associated fibronectin type‐III domain‐containing protein A (FNDC3A) and FNDC3B, FAM46C remodels the trafficking and secretion of myeloma cells, which induces ER stress and impairs autophagy, eventually causing apoptosis [ 29 , 30 ]. Moreover, FAM46C is reported to physically interact with polo‐like kinase 4 (PLK4) and inhibits its kinase activity, thereby suppressing colorectal cancer in a PAP activity‐independent manner [ 31 ].…”

Identification of a Novel Gene Model-Based Homologous Recombination Deficiency Score to Improve Survival Prediction of TNBC.

“…Family with sequence similarity 46, member C (FAM46C) is a member of the FAM46 family, it is located on chromosome 1p12 and seems to play a role in the regulation of translation by acting as an mRNA stabilizing factor. its abnormal deletions in tumor tissues were con rmed in multiple myeloma [20] and gastric cancer [21]. Zhang, et al reported that FAM46C was downregulated in hepatocellular carcinoma (HCC)and induced cell apoptosis through regulating Ras/MEK/ERK pathway [22].…”