SUN-138 Functional Characterization of Tumor-Associated Germline TMEM127 Variants Reveals Novel Insights into Membrane Topology and Protein Trafficking
Year: 2020
Type: article
Abstract: ABSTRACT Purpose To better understand the function of the transmembrane protein TMEM127, a poorly known tumor suppressor gene associated with pheochromocytomas, paragangliomas and renal carcinomas, we evaluated patient-derived germline variants. Methods Subcellular localization and steady-state levels of 21 tumor-associated, transiently expressed TMEM127 variants were compared to the wild-type protein using immunofluorescence and immunoblot analysis, respectively, in cells genetically modified to lack endogenous TMEM127. Membrane topology and endocytic mechanisms were also assessed. Results We identified three subgroups of mutations and determined that 15 of the 21 variants (71%), including 9 of 15 missense variants (60%), are pathogenic or likely pathogenic, through loss of membrane binding ability, stability and/or internalization capability. Investigation into an N-terminal cluster of missense variants uncovered a previously unrecognized transmembrane domain, indicating that TMEM127 is a four-, not a three-, transmembrane domain-containing protein. Additionally, a C-terminal variant with predominant plasma membrane localization revealed an atypical, extended acidic, dileucine-based motif required for TMEM127 internalization through clathrin-mediated endocytosis. Conclusion We characterized the functional deficits of several germline TMEM127 variants and identified novel structure-function features of TMEM127, namely, a fourth transmembrane domain and an endocytic motif. These findings will assist in TMEM127 variant interpretation and will help guide future studies investigating the cellular role of TMEM127.
Source: Journal of the Endocrine Society
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,255
Funders: Alex's Lemonade Stand Foundation for Childhood Cancer, Cancer Prevention and Research Institute of Texas, Leukemia and Lymphoma Society, Georgia Clinical and Translational Science Alliance, Central South University, National Institutes of Health, University of Texas Health Science Center at San Antonio, Center for Long-Term Cybersecurity, University of California Berkeley, National Institute on Aging, National Cancer Institute, National Institute of General Medical Sciences, National Center for Advancing Translational Sciences
Awards: G1114781936, Mays Cancer Center at UT Health SA, G1351874825, G1560266550, G1891014043, G2361851875, G2444532981, G2446443270, G3078496993, G3190443648, G3248514885, G3362354542, Institute for Integration of Medicine & Science: A Partnership to Improve Health, G3614813735, G3867857540, G3934442055, Mechanisms of internalization and trafficking of the tumor suppressor and lysosomal membrane protein TMEM127, G4642960861, G5024421730, G5057425288, G5550184716, G6040293822, G6655026610, UTHSCSA Cancer Research Training Program, B cell receptor signaling intersects with angiogenesis in diffuse large B cell lymphoma, G7805825262, Institute for Integration of Medicine & Science: A Partnership to Improve Health, G9000150452, Cancer Biology Training Program
OpenAlex ID: W3023917245