title: Enhanced sensitivity to DSS colitis caused by a hypomorphic Mbtps1 mutation disrupting the ATF6-driven unfolded protein response.
abstract: Here, we describe an N-ethyl-N-nitrosourea (ENU)-induced missense error in the membrane-bound transcription factor peptidase site 1 (S1P)-encoding gene (Mbtps1) that causes enhanced susceptibility to dextran sodium sulfate (DSS)-induced colitis. S1P cleaves and activates cAMP response element binding protein/ATF transcription factors, the sterol regulatory element-binding proteins (SREBPs), and other proteins of both endogenous and viral origin. Because S1P has a nonredundant function in the ATF6-dependent unfolded protein response (UPR), woodrat mice show diminished levels of major endoplasmic reticulum chaperones GRP78 (BiP) and GRP94 in the colon upon DSS administration. Experiments with bone marrow chimeric mice reveal a requirement for S1P in nonhematopoietic cells, without which a diminished UPR and colitis develop.
authors.affiliation: Department of Genetics, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Katharina
authors.initials: K
authors.lastname: Brandl
authors.forename: Sophie
authors.initials: S
authors.lastname: Rutschmann
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Du
authors.forename: Nengming
authors.initials: N
authors.lastname: Xiao
authors.forename: Bernd
authors.initials: B
authors.lastname: Schnabl
authors.forename: David A
authors.initials: DA
authors.lastname: Brenner
authors.forename: Bruce
authors.initials: B
authors.lastname: Beutler
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism*; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D016264:Dextran Sulfate / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D043484:Proprotein Convertases; D017510:Protein Folding; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D016264:Dextran Sulfate; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C115575:membrane-bound transcription factor peptidase, site 1