Absence of the ER Cation Channel TMEM38B/TRIC-B Disrupts Intracellular Calcium Homeostasis and Dysregulates Collagen Synthesis in Recessive Osteogenesis Imperfecta.
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...
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Public Library of Science (PLoS)
2016-07-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1006156&type=printable |
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| author | 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 |
| author_facet | 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 |
| author_sort | Wayne A Cabral |
| collection | DOAJ |
| description | 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 IP3R-mediated Ca2+ 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 Ca2+, associated with deficient store-operated calcium entry, although SERCA and IP3R have normal stability. Notably, steady state ER Ca2+ is unchanged in TRIC-B deficiency, supporting a role for TRIC-B in the kinetics of ER calcium depletion and recovery. The disturbed Ca2+ 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 Ca2+-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 Ca2+ 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. |
| format | Article |
| id | doaj-art-658422182509483ea7dca5eabb1f1822 |
| institution | DOAJ |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2016-07-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Genetics |
| spelling | doaj-art-658422182509483ea7dca5eabb1f18222025-08-20T02:45:37ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042016-07-01127e100615610.1371/journal.pgen.1006156Absence of the ER Cation Channel TMEM38B/TRIC-B Disrupts Intracellular Calcium Homeostasis and Dysregulates Collagen Synthesis in Recessive Osteogenesis Imperfecta.Wayne A CabralMasaki IshikawaMatthias GartenElena N MakareevaBrandi M SargentMaryAnn WeisAileen M BarnesEmma A WebbNicholas J ShawLeena Ala-KokkoFelicitas L LacbawanWolfgang HöglerSergey LeikinPaul S BlankJoshua ZimmerbergDavid R EyreYoshihiko YamadaJoan C MariniRecessive 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 IP3R-mediated Ca2+ 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 Ca2+, associated with deficient store-operated calcium entry, although SERCA and IP3R have normal stability. Notably, steady state ER Ca2+ is unchanged in TRIC-B deficiency, supporting a role for TRIC-B in the kinetics of ER calcium depletion and recovery. The disturbed Ca2+ 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 Ca2+-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 Ca2+ 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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1006156&type=printable |
| spellingShingle | 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 Absence of the ER Cation Channel TMEM38B/TRIC-B Disrupts Intracellular Calcium Homeostasis and Dysregulates Collagen Synthesis in Recessive Osteogenesis Imperfecta. PLoS Genetics |
| title | Absence of the ER Cation Channel TMEM38B/TRIC-B Disrupts Intracellular Calcium Homeostasis and Dysregulates Collagen Synthesis in Recessive Osteogenesis Imperfecta. |
| title_full | Absence of the ER Cation Channel TMEM38B/TRIC-B Disrupts Intracellular Calcium Homeostasis and Dysregulates Collagen Synthesis in Recessive Osteogenesis Imperfecta. |
| title_fullStr | Absence of the ER Cation Channel TMEM38B/TRIC-B Disrupts Intracellular Calcium Homeostasis and Dysregulates Collagen Synthesis in Recessive Osteogenesis Imperfecta. |
| title_full_unstemmed | Absence of the ER Cation Channel TMEM38B/TRIC-B Disrupts Intracellular Calcium Homeostasis and Dysregulates Collagen Synthesis in Recessive Osteogenesis Imperfecta. |
| title_short | Absence of the ER Cation Channel TMEM38B/TRIC-B Disrupts Intracellular Calcium Homeostasis and Dysregulates Collagen Synthesis in Recessive Osteogenesis Imperfecta. |
| title_sort | absence of the er cation channel tmem38b tric b disrupts intracellular calcium homeostasis and dysregulates collagen synthesis in recessive osteogenesis imperfecta |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1006156&type=printable |
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