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Site-1 protease deficiency causes human skeletal dysplasia due to defective inter-organelle protein trafficking
Yuji Kondo, … , Patrick M. Gaffney, Lijun Xia
Yuji Kondo, … , Patrick M. Gaffney, Lijun Xia
Published July 26, 2018
Citation Information: JCI Insight. 2018;3(14):e121596. https://doi.org/10.1172/jci.insight.121596.
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Research Article Cell biology Genetics

Site-1 protease deficiency causes human skeletal dysplasia due to defective inter-organelle protein trafficking

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Abstract

Site-1 protease (S1P), encoded by MBTPS1, is a serine protease in the Golgi. S1P regulates lipogenesis, endoplasmic reticulum (ER) function, and lysosome biogenesis in mice and in cultured cells. However, how S1P differentially regulates these diverse functions in humans has been unclear. In addition, no human disease with S1P deficiency has been identified. Here, we report a pediatric patient with an amorphic and a severely hypomorphic mutation in MBTPS1. The unique combination of these mutations results in a frequency of functional MBTPS1 transcripts of approximately 1%, a finding that is associated with skeletal dysplasia and elevated blood lysosomal enzymes. We found that the residually expressed S1P is sufficient for lipid homeostasis but not for ER and lysosomal functions, especially in chondrocytes. The defective S1P function specifically impairs activation of the ER stress transducer BBF2H7, leading to ER retention of collagen in chondrocytes. S1P deficiency also causes abnormal secretion of lysosomal enzymes due to partial impairment of mannose-6-phosphate–dependent delivery to lysosomes. Collectively, these abnormalities lead to apoptosis of chondrocytes and lysosomal enzyme–mediated degradation of the bone matrix. Correction of an MBTPS1 variant or reduction of ER stress mitigated collagen-trafficking defects. These results define a new congenital human skeletal disorder and, more importantly, reveal that S1P is particularly required for skeletal development in humans. Our findings may also lead to new therapies for other genetic skeletal diseases, as ER dysfunction is common in these disorders.

Authors

Yuji Kondo, Jianxin Fu, Hua Wang, Christopher Hoover, J. Michael McDaniel, Richard Steet, Debabrata Patra, Jianhua Song, Laura Pollard, Sara Cathey, Tadayuki Yago, Graham Wiley, Susan Macwana, Joel Guthridge, Samuel McGee, Shibo Li, Courtney Griffin, Koichi Furukawa, Judith A. James, Changgeng Ruan, Rodger P. McEver, Klaas J. Wierenga, Patrick M. Gaffney, Lijun Xia

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Figure 5

Impaired S1P-BBF2H7-Tango1 axis causes abnormal collagen retention in the ER.

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Impaired S1P-BBF2H7-Tango1 axis causes abnormal collagen retention in th...
(A) Quantification of mean fluorescent intensity (MFI) of immunofluorescence images of collagen I in fibroblasts treated with or without TGF-β1 treatment for 48 hours. Regardless of TGF-β1 treatment, the patient fibroblasts showed accumulation of collagen-I. (B) Transmission electron microscopy (TEM) images of maternal and patient fibroblasts. Arrowheads indicate rough ER. Enlarged rough ER was found in patient fibroblasts compared with maternal fibroblasts. Scale bar: 500 nm. (C) Expression of COP-II mega vesicle-related genes in maternal and patient-derived fibroblasts, as measured by qRT-PCR, normalized to maternal fibroblasts. (D) Expression of collagen I (COL1A1), ER stress-related genes (HSPA5 and DDIT3), and COP-II component (SEC23A) genes in maternal and patient fibroblasts, by qRT-PCR normalized to maternal fibroblasts treated with or without TGF-β1. Compared with maternal cells, patient cells showed defective induction of UPR triggered by TGF-β1 treatment. (E) Western blotting of Sec23a, Tango1, and Hsp47 in fibroblasts. Mo., maternal fibroblasts; PF, PF-429242 (S1P inhibitor). (F) Secreted procollagen I from maternal and patient fibroblasts, treated as indicated, was measured by ELISA. PF, PF-429242. S1P-dependent collagen-I secretion is shown. (G) Schematic protein domain structures of BBF2H7 and the constitutively active BBF2H7 p60 mutant. S1P cleaves the luminal domain of BBF2H7 followed by cleavage of the transmembrane domain by S2P in the Golgi apparatus, resulting in translocation of the cytoplasmic domain of BBF2H7 (BBF2H7 p60) to the nucleus to promote gene expression. (H) Expression of COL1A1, HSPA5, DDIT3, OASIS (CREB3L1), SEC23A, and COP-II–enlarging proteins (Sedlin, Tango1, and Hsp47) in BBF2H7 p60-expressing patient fibroblasts compared with uninfected cells as analyzed by quantitative RT-PCR. All data are from 3 independent experiments. *P < 0.05; **P < 0.01, Student’s t test.

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