Ceramide-Induced Alternative Translocation of TM4SF20
Lee, Ching En
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The polytopic membrane protein TM4SF20 (transmembrane 4 L6 family 20) is a protein containing four transmembrane helices that inhibits the Regulated Intramembrane Proteolysis (RIP) of the transcriptional factor CREB3L1 (cAMP response element binding protein 3-like 1), a transcription factor synthesized as a membrane-bound precursor. CREB3L1 RIP is induced by several stimuli: ER stress, viral infections, the chemotherapeutic drug, doxorubicin, and the sphingolipid, ceramide. Additionally, TGF-β (transforming growth factor-β), a cytokine known to stimulate collagen production, induces the proteolytic activation of CREB3L1 in human A549 cells through inhibition of TM4SF20 expression, which normally inhibits RIP of CREB3L1. We also find that the TM4SF20 regulation of CREB3L1 RIP is regulated by ceramide. In this study we find that ceramide can regulate the ability of first transmembrane domain of TM4SF20 to determine its orientation in the membrane. Under normal conditions, TM4SF20 is synthesized as a protein that inhibits the cleavage of CREB3L1 when TRAM2 (translocation associated membrane protein 2) is associated with the ER translocon. Excess ceramide dissociates TRAM2 from the ER translocon such that the N-terminus of TM4SF20 can no longer be forced by the first transmembrane domain to function as a signal peptide. Under excess ceramide conditions, TM4SF20 adopts a completely opposite topology and allows the cleavage of CREB3L1 to proceed. We have designated this novel mechanism for transmembrane protein regulation as "alternative translocation."