Site-1 and site-2 proteases: A team of two in regulated proteolysis

Danyukova, Tatyana; Schöneck, Kenneth; Pohl, Sandra

doi:10.1016/j.bbamcr.2021.119138

Cited by 18 publications

(15 citation statements)

References 106 publications

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“…The best-studied transmembrane signaling mechanism by ECF anti-σ factors is the regulated intramembrane proteolysis (RIP) ( 16 ). RIP was first described for controlling cholesterol metabolism in mammals ( 17 ) and was found in many signaling processes of species from bacteria to mammals ( 18 , 19 ). The RIP process of bacterial ECF anti-σ factors involves sequential cleavages of the anti-σ factor by cascade proteases (site-1 protease, site-2 protease, etc.)…”

Section: Introductionmentioning

confidence: 99%

Essential autoproteolysis of bacterial anti-σ factor RsgI for transmembrane signal transduction

Chen,

Dong,

et al. 2023

Sci. Adv.

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Autoproteolysis has been discovered to play key roles in various biological processes, but functional autoproteolysis has been rarely reported for transmembrane signaling in prokaryotes. In this study, an autoproteolytic effect was discovered in the conserved periplasmic domain of anti-σ factor RsgIs from Clostridium thermocellum , which was found to transmit extracellular polysaccharide-sensing signals into cells for regulation of the cellulosome system, a polysaccharide-degrading multienzyme complex. Crystal and NMR structures of periplasmic domains from three RsgIs demonstrated that they are different from all known proteins that undergo autoproteolysis. The RsgI-based autocleavage site was located at a conserved Asn-Pro motif between the β1 and β2 strands in the periplasmic domain. This cleavage was demonstrated to be essential for subsequent regulated intramembrane proteolysis to activate the cognate SigI, in a manner similar to that of autoproteolysis-dependent activation of eukaryotic adhesion G protein–coupled receptors. These results indicate the presence of a unique prevalent type of autoproteolytic phenomenon in bacteria for signal transduction.

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Section: Introductionmentioning

confidence: 99%

Essential autoproteolysis of bacterial anti-σ factor RsgI for transmembrane signal transduction

Chen,

Dong,

et al. 2023

Sci. Adv.

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“…1f, g ). MBTPS1 encodes site-1 protease (S1P), a Golgi-resident serine protease that is responsible for the proteolytic cleavage of multiple substrates, including GNPTAB, SREBP1/2, and ATF6 29 , 30 . GNPTAB and GNPTG encode the three subunits of the GNPT enzyme 31 , which requires S1P cleavage for its activation and is responsible for adding M6P to the lysosomal enzymes (Fig.…”

Section: Resultsmentioning

confidence: 99%

GCAF(TMEM251) regulates lysosome biogenesis by activating the mannose-6-phosphate pathway

Zhang

Yang

et al. 2022

Nat Commun

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The mannose-6-phosphate (M6P) biosynthetic pathway for lysosome biogenesis has been studied for decades and is considered a well-understood topic. However, whether this pathway is regulated remains an open question. In a genome-wide CRISPR/Cas9 knockout screen, we discover TMEM251 as the first regulator of the M6P modification. Deleting TMEM251 causes mistargeting of most lysosomal enzymes due to their loss of M6P modification and accumulation of numerous undigested materials. We further demonstrate that TMEM251 localizes to the Golgi and is required for the cleavage and activity of GNPT, the enzyme that catalyzes M6P modification. In zebrafish, TMEM251 deletion leads to severe developmental defects including heart edema and skeletal dysplasia, which phenocopies Mucolipidosis Type II. Our discovery provides a mechanism for the newly discovered human disease caused by TMEM251 mutations. We name TMEM251 as GNPTAB cleavage and activity factor (GCAF) and its related disease as Mucolipidosis Type V.

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“…The two proteins interact, are spatially co-localized to the Golgi, and as we demonstrate here also undergo bi-directional intermolecular proteolysis which can be inhibited pharmacologically or by introducing S1P cleavage-disrupting mutations. Functionally, SPRING is needed for maximal proteolytic activation of SREBPs, ATF6, CREB3L3, and GNTAB that are all native S1P substrates (11,15). Our current study supports findings by Xiao et al .…”

Section: Discussionmentioning

confidence: 99%

“…In its active form, S1P cleaves several proproteins at the C-terminus of the consensus motif RX(L,V,I)Z↓, whereby X can be any amino acid, excluding Pro or Cys and Z is any residue (preferably Leu) except Val, Pro, Cys, or Glu (11,14). Accordingly, S1P is implicated in the cleavage-dependent activation of, amongst others, several transcription factors (11,15). Other than SREBP1 and 2 (1,10), those include ER stress response related transcription factors like activating transcription factor 6 (ATF6) (16,17), cyclic AMP-responsive element binding proteins CREB3 (18), CREB3L1 (19), CREB4 (20), and CREB3L3 (21).…”

Section: Introductionmentioning

confidence: 99%

Intermolecular proteolytic processing of SPRING and Site-1-protease regulate SREBP signaling

Hendrix

Tan

Ndoj

et al. 2023

Preprint

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The SREBP transcription factors are central regulators of fatty acid and cholesterol metabolism. Produced as membrane-resident precursor proteins in the ER, their transcriptional activation requires the cholesterol-dependent translocation to the Golgi, and subsequent proteolytic cleavage by S1P, a type-I transmembrane protein. S1P is produced as a proprotein convertase that needs to undergo autocatalytic cleavage to attain its mature form in the Golgi, in a process that is not fully elucidated. We have recently identified SPRING (C12ORF49) as a novel regulator of the SREBP pathway and reported that S1P activity and retrograde recycling of the SREBP chaperone SCAP are affected. Here, we demonstrate that SPRING and S1P interact and that in co-transfection experiments in mammalian cells this facilitates the autocatalytic activation of S1PA to C form. Accordingly, S1PA to C processing of stably overexpressed S1P in SPRINGKO cells is attenuated, but not abolished, and does not rescue SREBP signaling. Reciprocally, we identified a conserved S1P cleavage site in SPRING, and demonstrate that cleavage of SPRING results in secretion of the SPRING ectodomain. SPRING cleavage is S1P-specific and can be pharmacologically inhibited by S1P inhibitors or by mutating the S1P cleavage site. Functional analysis revealed that the SPRING ectodomain was sufficient to support S1PA to C processing and SREBP signaling, but that SPRING cleavage is not a prerequisite for this. In conclusion, our study reveals a complex interplay between the proteolytic activation of S1P and SPRING yet suggests that this is not the primary mechanism underlying the role of SPRING in SREBP signaling.

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Site-1 and site-2 proteases: A team of two in regulated proteolysis

Cited by 18 publications

References 106 publications

Essential autoproteolysis of bacterial anti-σ factor RsgI for transmembrane signal transduction

Essential autoproteolysis of bacterial anti-σ factor RsgI for transmembrane signal transduction

GCAF(TMEM251) regulates lysosome biogenesis by activating the mannose-6-phosphate pathway

Intermolecular proteolytic processing of SPRING and Site-1-protease regulate SREBP signaling

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