Characterizing the molecular functions of TENT5/FAM46 proteins

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2021

The secretory pathway is the route whereby newly synthetized proteins are released in the extracellular space or delivered to the plasma membrane. This process has essential roles in cell, tissue and organ homeostasis, development and function. Thus, protein secretion is a driving force in the evolution of complex organisms and tissue specialization. All cells express secretory proteins; however, some cells are professionally committed to protein secretion like plasma cells, specialized in antibody production. TENT5/FAM46 is a poorly characterized family of 4 (A to D) proteins that selectively stabilize mRNAs encoding proteins directed to the secretory apparatus, increasing in this way the secretory activity. In line, FAM46 proteins cause or are associated with different human diseases related to secretory cells. Mutations in FAM46A are responsible for a rare form of osteogenesis imperfecta caused by defective collagen deposition by osteoblasts, FAM46B expression is associated with refractory lupus nephritis, whereas FAM46C is mutated in up to 20% of patients with multiple myeloma, the cancer of plasma cells. Of note, our recent study indicates that myeloma cells aim to lose FAM46C to reduce antibody production and the resulting stress, saving energy for proliferation. However, in line with the heterogeneity of associated diseases, our data showed that FAM46 members displays high variability on their cellular localization and effects, with still many unexplored aspects including the physiological role of FAM46B. This lack of knowledge limits the design of FAM46-related therapeutic strategies and our possibilities to exploit FAM46 proteins as natural tuner of protein secretion. The goal of this project is to comprehensively dissect the biological functions and associated molecular circuits of all FAM46 members and to test their pathophysiologic relevance and therapeutic potential in models of a disease of compromised ER transport (CMT1B) and multiple myeloma.