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

  • PLoS Genet. 2016 Apr 27;12(4):e1006002. doi: 10.1371/journal.pgen.1006002.
Melissa E Heard  1 ,  Roberta Besio  1 ,  MaryAnn Weis  2 ,  Jyoti Rai  2 ,  David M Hudson  2 ,  Milena Dimori  1 ,  Sarah M Zimmerman  1 ,  Jeffrey A Kamykowski  1 ,  William R Hogue  3 ,  Frances L Swain  3 ,  Marie S Burdine  4 ,  Samuel G Mackintosh  4 ,  Alan J Tackett  4 ,  Larry J Suva  3 ,  David R Eyre  2 ,  Roy Morello  1  5
Affiliations
  • 1. Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
  • 2. Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, Washington, United States of America.
  • 3. Department of Orthopaedic Surgery, Center for Orthopaedic Research, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
  • 4. Department of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
  • 5. Division of Genetics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
PMID: 27119146 DOI: 10.1371/journal.pgen.1006002
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.