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TISP40, a mouse spermatid-specific gene, encodes a CREB/CREM family transcription factor that is predominantly expressed during spermiogenesis. We report here that TISP40 generates two types of proteins, Tisp40α and Tisp40β, both of which contain a transmembrane domain and localize to the endoplasmic reticulum (ER). In contrast, mutant proteins lacking the transmembrane domain (Tisp40α/βΔTM) primarily localize to the nucleus. Endoglycosidase H treatment shows that the C-terminus of Tisp40α/β is glycosylated. Protease experiments demonstrate that Tisp40α/β are Type II transmembrane proteins that are released into the nucleus by a two-step cleavage mechanism called ‘regulated intramembrane proteolysis’ (Rip). Unlike previously published observations, Tisp40α does not bind to the NF-κB site; instead, it specifically binds to the unfolded protein response element (UPRE). Luciferase assays reveal that Tisp40βΔTM activates transcription through UPRE. Northern blot analysis shows that Tisp40α/βΔTM proteins up-regulate EDEM (ER degradation of enhancing α-manosidase-like protein) mRNA. These observations unveil a novel event in mouse spermiogenesis and show that the final stage of trans-criptional regulation is controlled by the Rip pathway.