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Tisp40, a spermatid specific bZip transcription factor, functions by binding to the unfolded protein response element via the Rip pathway.

Nagamori I., Yabuta N., Fujii T., Tanaka H., Yomogida K., Nishimune Y., Nojima H.

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, Tisp40alpha and Tisp40beta, both of which contain a transmembrane domain and localize to the endoplasmic reticulum (ER). In contrast, mutant proteins lacking the transmembrane domain (Tisp40alpha/betaDeltaTM) primarily localize to the nucleus. Endoglycosidase H treatment shows that the C-terminus of Tisp40alpha/beta is glycosylated. Protease experiments demonstrate that Tisp40alpha/beta 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, Tisp40alpha does not bind to the NF-kappaB site; instead, it specifically binds to the unfolded protein response element (UPRE). Luciferase assays reveal that Tisp40betaDeltaTM activates transcription through UPRE. Northern blot analysis shows that Tisp40alpha/betaDeltaTM proteins up-regulate EDEM (ER degradation of enhancing alpha-manosidase-like protein) mRNA. These observations unveil a novel event in mouse spermiogenesis and show that the final stage of transcriptional regulation is controlled by the Rip pathway.

Genes Cells 10:575-594(2005) [PubMed] [Europe PMC]