Publikationsdatum:
2016-07-22
Beschreibung:
by Wayne A. Cabral, Masaki Ishikawa, Matthias Garten, Elena N. Makareeva, Brandi M. Sargent, MaryAnn Weis, Aileen M. Barnes, Emma A. Webb, Nicholas J. Shaw, Leena Ala-Kokko, Felicitas L. Lacbawan, Wolfgang Högler, Sergey Leikin, Paul S. Blank, Joshua Zimmerberg, David R. Eyre, Yoshihiko Yamada, Joan C. Marini Recessive osteogenesis imperfecta (OI) is caused by defects in proteins involved in post-translational interactions with type I collagen. Recently, a novel form of moderately severe OI caused by null mutations in TMEM38B was identified. TMEM38B encodes the ER membrane monovalent cation channel, TRIC-B, proposed to counterbalance IP 3 R-mediated Ca 2+ release from intracellular stores. The molecular mechanisms by which TMEM38B mutations cause OI are unknown. We identified 3 probands with recessive defects in TMEM38B . TRIC-B protein is undetectable in proband fibroblasts and osteoblasts, although reduced TMEM38B transcripts are present. TRIC-B deficiency causes impaired release of ER luminal Ca 2+ , associated with deficient store-operated calcium entry, although SERCA and IP 3 R have normal stability. Notably, steady state ER Ca 2+ is unchanged in TRIC-B deficiency, supporting a role for TRIC-B in the kinetics of ER calcium depletion and recovery. The disturbed Ca 2+ flux causes ER stress and increased BiP, and dysregulates synthesis of proband type I collagen at multiple steps. Collagen helical lysine hydroxylation is reduced, while telopeptide hydroxylation is increased, despite increased LH1 and decreased Ca 2+ -dependent FKBP65, respectively. Although PDI levels are maintained, procollagen chain assembly is delayed in proband cells. The resulting misfolded collagen is substantially retained in TRIC-B null cells, consistent with a 50–70% reduction in secreted collagen. Lower-stability forms of collagen that elude proteasomal degradation are not incorporated into extracellular matrix, which contains only normal stability collagen, resulting in matrix insufficiency. These data support a role for TRIC-B in intracellular Ca 2+ homeostasis, and demonstrate that absence of TMEM38B causes OI by dysregulation of calcium flux kinetics in the ER, impacting multiple collagen-specific chaperones and modifying enzymes.
Print ISSN:
1553-7390
Digitale ISSN:
1553-7404
Thema:
Biologie
Permalink