title: Cartilage-specific ablation of site-1 protease in mice results in the endoplasmic reticulum entrapment of type IIb procollagen and down-regulation of cholesterol and lipid homeostasis.
abstract: The proprotein convertase site-1 protease (S1P) converts latent ER-membrane bound transcription factors SREBPs and ATF6 to their active forms. SREBPs are involved in cholesterol and fatty acid homeostasis whereas ATF6 is involved in unfolded protein response pathways (UPR). Cartilage-specific ablation of S1P in mice (S1Pcko) results in abnormal cartilage devoid of type II collagen protein (Col II). S1Pcko mice also lack endochondral bone development. To analyze S1Pcko cartilage we performed double-labeled immunofluorescence studies for matrix proteins that demonstrated that type IIB procollagen is trapped inside the ER in S1Pcko chondrocytes. This retention is specific to type IIB procollagen; other cartilage proteins such as type IIA procollagen, cartilage oligomeric matrix protein (COMP) and aggrecan are not affected. The S1Pcko cartilage thus exhibits COMP-, aggrecan-, and type IIA procollagen-derived matrices but is characterized by the absence of a type IIB procollagen-derived matrix. To understand the molecular reason behind S1Pcko phenotypes we performed genome-wide transcriptional profiling of cartilage isolated from S1Pcko and wild type littermates. While the UPR pathways are unaffected, the SREBPs-directed cholesterol and fatty acid pathways are significantly down-regulated in S1Pcko chondrocytes, with maximal down-regulation of the stearoyl-CoA desaturase-1 (Scd1) gene. However, mouse models that lack Scd1 or exhibit reduction in lipid homeostasis do not suffer from the ER retention of Col II or lack endochondral bone. These studies indicate an indispensable role for S1P in type IIB procollagen trafficking from the ER. This role appears not to be related to lipid pathways or other current known functions of S1P and is likely dependent on additional, yet unknown, S1P substrates in chondrocytes.
authors.affiliation: Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Debabrata
authors.initials: D
authors.lastname: Patra
authors.affiliation: Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: DeLassus
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Guosheng
authors.initials: G
authors.lastname: Liang
authors.affiliation: Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, United States of America; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Sandell
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002356:Cartilage / Q000378:metabolism*; D064236:Cartilage Oligomeric Matrix Protein / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000502:physiology; D043484:Proprotein Convertases / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D064236:Cartilage Oligomeric Matrix Protein; D024043:Collagen Type II; D051779:Sterol Regulatory Element Binding Proteins; D002784:Cholesterol; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C115575:membrane-bound transcription factor peptidase, site 1