Recombinant Human Membrane-bound transcription factor site-1 protease (MBTPS1), partial

Function

Serine protease that cleaves after hydrophobic or small residues, provided that Arg or Lys is in position P4: known substrates include SREBF1/SREBP1, SREBF2/SREBP2, BDNF, GNPTAB, ATF6, ATF6B and FAM20C (PubMed:10644685, PubMed:12782636, PubMed:21719679, PubMed:34349020). Cleaves substrates after Arg-Ser-Val-Leu (SREBP2), Arg-His-Leu-Leu (ATF6), Arg-Gly-Leu-Thr (BDNF) and its own propeptide after Arg-Arg-Leu-Leu (PubMed:10644685, PubMed:21719679). Catalyzes the first step in the proteolytic activation of the sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2 (PubMed:12782636). Also mediates the first step in the proteolytic activation of the cyclic AMP-dependent transcription factor ATF-6 (ATF6 and ATF6B) (PubMed:12782636). Mediates the protein cleavage of GNPTAB into subunit alpha and beta, thereby participating in biogenesis of lysosomes (PubMed:21719679). Cleaves the propeptide from FAM20C which is required for FAM20C secretion from the Golgi apparatus membrane and for enhancement of FAM20C kinase activity, promoting osteoblast differentiation and biomineralization (PubMed:34349020). Involved in the regulation of M6P-dependent Golgi-to-lysosome trafficking of lysosomal enzymes (PubMed:21719679, PubMed:30046013). It is required for the activation of CREB3L2/BBF2H7, a transcriptional activator of MIA3/TANGO and other genes controlling mega vesicle formation (PubMed:30046013). Therefore, it plays a key role in the regulation of mega vesicle-mediated collagen trafficking (PubMed:30046013). Promotes FAD binding to the ETFA/ETFB complex and is therefore involved in mitochondrial respiratory chain regulation (PubMed:35362222). In astrocytes and osteoblasts, upon DNA damage and ER stress, mediates the first step of the regulated intramembrane proteolytic activation of the transcription factor CREB3L1, leading to the inhibition of cell-cycle progression (PubMed:16417584)

Subcellular Location

Endoplasmic reticulum membrane (Single-pass type I membrane protein); Golgi apparatus membrane (Single-pass type I membrane protein); Secreted; Mitochondrion

Disease Association

Spondyloepiphyseal dysplasia, Kondo-Fu type (SEDKF) : A disorder characterized by severely retarded growth, spondyloepiphyseal dysplasia, reduced bone mineral density, and markedly elevated plasma levels of various lysosomal enzymes. Additional features include pectus carinatum, kyphosis, a waddling gait, brachydactyly and dysmorphic facial features. SEDKF transmission pattern is consistent with autosomal recessive inheritance. [The disease is caused by variants affecting the gene represented in this entry] | Cataract, alopecia, oral mucosal disorder, and psoriasis-like syndrome (CAOP) : An autosomal recessive disorder characterized by early-onset bilateral lens cataract, generalized non-scarring alopecia, oral mucosal disorder, and severe psoriasiform skin lesions affecting the scalp, facial, inguinal region, buttocks, and lower extremities. [The disease is caused by variants affecting the gene represented in this entry]

Tissue Specificity

Widely expressed

Subunit

Interacts with LYSET; this interaction bridges GNPTAB to MBTPS1. Forms a complex with ETFA and ETFB; the interaction stabilizes the ETFA/ETFB heterodimer, promotes FAD binding to ETFA/ETFB and is independent of MBTPS1 proteolytic activity (PubMed:35362222)

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