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

Debabrata Patra, Elizabeth DeLassus, Guosheng Liang, Linda J. Sandell

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 (S1P<sup>cko</sup>) results in abnormal cartilage devoid of type II collagen protein (Col II). S1P<sup>cko</sup> mice also lack endochondral bone development. To analyze S1P<sup>cko</sup> cartilage we performed double-labeled immunofluorescence studies for matrix proteins that demonstrated that type IIB procollagen is trapped inside the ER in S1P<sup>cko</sup> 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 S1P<sup>cko</sup> 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 S1P<sup>cko</sup> phenotypes we performed genome-wide transcriptional profiling of cartilage isolated from S1P<sup>cko</sup> and wild type littermates. While the UPR pathways are unaffected, the SREBPs-directed cholesterol and fatty acid pathways are significantly down-regulated in S1P <sup>cko</sup> 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.

Original languageEnglish (US)
Article numbere105674
JournalPLoS One
Volume9
Issue number8
DOIs
StatePublished - Aug 22 2014

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Procollagen
Cartilage
Ablation
cartilage
Endoplasmic Reticulum
endoplasmic reticulum
homeostasis
Homeostasis
proteinases
Down-Regulation
Cholesterol
cholesterol
Lipids
mice
lipids
Chondrocytes
Cartilage Oligomeric Matrix Protein
Stearoyl-CoA Desaturase
Unfolded Protein Response
Aggrecans

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

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. / Patra, Debabrata; DeLassus, Elizabeth; Liang, Guosheng; Sandell, Linda J.

In: PLoS One, Vol. 9, No. 8, e105674, 22.08.2014.

Research output: Contribution to journalArticle

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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 S1P cko 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.",
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