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Sc65-Null Mice Provide Evidence for a Novel Endoplasmic Reticulum Complex Regulating Collagen Lysyl Hydroxylation.

ABSTRACT: Collagen is a major component of the extracellular matrix and its integrity is essential for connective tissue and organ function. The importance of proteins involved in intracellular collagen post-translational modification, folding and transport was recently highlighted from studies on recessive forms of osteogenesis imperfecta (OI). Here we describe the critical role of SC65 (Synaptonemal Complex 65, P3H4), a leprecan-family member, as part of an endoplasmic reticulum (ER) complex with prolyl 3-hydroxylase 3. This complex affects the activity of lysyl-hydroxylase 1 potentially through interactions with the enzyme and/or cyclophilin B. Loss of Sc65 in the mouse results in instability of this complex, altered collagen lysine hydroxylation and cross-linking leading to connective tissue defects that include low bone mass and skin fragility. This is the first indication of a prolyl-hydroxylase complex in the ER controlling lysyl-hydroxylase activity during collagen synthesis.

SUBMITTER: Heard ME

PROVIDER: S-EPMC4847768 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Sc65-Null Mice Provide Evidence for a Novel Endoplasmic Reticulum Complex Regulating Collagen Lysyl Hydroxylation.

Heard Melissa E ME Besio Roberta R Weis MaryAnn M Rai Jyoti J Hudson David M DM Dimori Milena M Zimmerman Sarah M SM Kamykowski Jeffrey A JA Hogue William R WR Swain Frances L FL Burdine Marie S MS Mackintosh Samuel G SG Tackett Alan J AJ Suva Larry J LJ Eyre David R DR Morello Roy R

PLoS genetics 20160427 4

Collagen is a major component of the extracellular matrix and its integrity is essential for connective tissue and organ function. The importance of proteins involved in intracellular collagen post-translational modification, folding and transport was recently highlighted from studies on recessive forms of osteogenesis imperfecta (OI). Here we describe the critical role of SC65 (Synaptonemal Complex 65, P3H4), a leprecan-family member, as part of an endoplasmic reticulum (ER) complex with prolyl ...[more]

PMID: 27119146

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Project description:Autophagy is reported to be involved in the formation of skin hypertrophic scar (HTS). However, the role of autophagy in the process of fibrosis remains unclear, therefore an improved understanding of the molecular mechanisms associated with autophagy may accelerate the development of effective therapeutic strategies against HTS. The present study evaluated the roles of autophagy mediated by transcription factor EB (TFEB), a pivotal regulator of lysosome biogenesis and autophagy, in transforming growth factor‑β1 (TGF‑β1)‑induced fibroblast differentiation and collagen production. Fibroblasts were treated with TGF‑β1, TGF‑β1 + tauroursodeoxycholic acid (TUDCA) or TGF‑β1 + TFEB‑small interfering RNA (siRNA). TGF‑β1 induced phenotypic transformation of fibroblasts, as well as collagen synthesis and secretion in fibroblasts in a dose‑dependent manner. Western blotting and immunofluorescence analyses demonstrated that TGF‑β1 upregulated the expression of autophagy‑related proteins through the endoplasmic reticulum (ER) stress pathway, whereas TUDCA reversed TGF‑β1‑induced changes. Reverse transcription‑quantitative PCR (RT‑qPCR), western blotting and RFP‑GFP‑LC3 double fluorescence analyses demonstrated that knockdown of TFEB by TFEB‑siRNA decreased autophagic flux, upregulated the expression of proteins involved in the apoptotic pathway, such as phosphorylated‑α subunit of eukaryotic initiation factor 2, C/EBP homologous protein and cysteinyl aspartate specific proteinase 3, and also downregulated the expression of α‑smooth muscle actin and collagen I (COL I) in fibroblasts. Immunofluorescence confocal analyses and enzyme‑linked immunosorbent assay indicated that TGF‑β1 increased the colocalization of COL I with lysosomal‑associated membrane protein 1 and Ras‑related protein Rab‑8A, a marker of secretory vesicles, in fibroblasts, as well as the secretion of pro‑COL Iα1 in culture supernatants. Meanwhile, these effects were abolished by TFEB knockdown. The present results suggested that autophagy reduced ER stress, decreased cell apoptosis and maintained fibroblast activation not only through degradation of misfolded or unfolded proteins, but also through promotion of COL I release from the autolysosome to the extracellular environment.

Dataset Information

Sc65-Null Mice Provide Evidence for a Novel Endoplasmic Reticulum Complex Regulating Collagen Lysyl Hydroxylation.

Publications

Sc65-Null Mice Provide Evidence for a Novel Endoplasmic Reticulum Complex Regulating Collagen Lysyl Hydroxylation.

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