ArticleJCI insight2018
Site-1 protease deficiency causes human skeletal dysplasia due to defective inter-organelle protein trafficking.
Article in JCI insight, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 58 citations in OpenAlex.
- Stress-induced secretory pathway disruption causes atypical metalloproteinase transport in PMM2-CDG.iScience · 2026Article
- Pi4ka downregulation triggers Creb3l2-dependent lysosomal dysfunction to promote maladaptive tubular remodeling and immune activation in acute kidney injury.Cell death & disease · 2026Article
- The intracellular localization and the ionic permeation of TRPV6 triggers chronic pancreatitis, skeletal dysplasia and is connected to mucolipidosis type II.Cell communication and signaling : CCS · 2025Article
- Site-1 protease-mediated cholesterol metabolism is essential for lymphatic development in mice.JCI insight · 2025Article
- SPRINGing off the lock: the role of SPRING in S1P activity and SREBP-regulated lipid metabolism.Current opinion in lipidology · 2025Review
- Site-1 protease is a negative regulator of sarcolipin promoter activity.Communications biology · 2025Article
- MBTPS1: a membrane-bound transcription factor protease implicated in the pathogenesis of several skin and skeletal disorders.Functional & integrative genomics · 2025Review
- Structural basis for substrate selectivity by site-one protease revealed by studies with a small-molecule inhibitor.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Update on the Genetics of Osteogenesis Imperfecta.Calcified tissue international · 2024Review
- S1P regulates intervertebral disc aging by mediating endoplasmic reticulum-mitochondrial calcium ion homeostasis.JCI insight · 2024Article
- Dominant missense variants in SREBF2 are associated with complex dermatological, neurological, and skeletal abnormalities.Genetics in medicine : official journal of the American College of Medical Genetics · 2024Article
- A genetically-encoded fluorescence-based reporter to spatiotemporally investigate mannose-6-phosphate pathway.Molecular biology of the cell · 2024Article
- SPRING licenses S1P-mediated cleavage of SREBP2 by displacing an inhibitory pro-domain.Nature communications · 2024Article
- Exome Sequencing Reveals Biallelic Mutations inDiagnostics (Basel, Switzerland) · 2024Article
- Article
- SPRING is a Dedicated Licensing Factor for SREBP-Specific Activation by S1P.Molecular and cellular biology · 2024Article
- Site-1 protease inhibits mitochondrial respiration by controlling the TGF-β target gene Mss51.Cell reports · 2023Article
- The factory, the antenna and the scaffold: the three-way interplay between the Golgi, cilium and extracellular matrix underlying tissue function.Biology open · 2023Review
- Case Report: Recombinant human growth hormone therapy in a patient with spondyloepiphyseal dysplasia, Kondo-Fu type.Frontiers in pediatrics · 2023Article
- Golgipathies reveal the critical role of the sorting machinery in brain and skeletal development.Nature communications · 2022Article
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Authors and funding
24 authors at 6 institutions in 3 countries.
Funding
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.
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