Complementation Cloning of , a Gene Encoding a Putative Metalloprotease Required for Intramembrane Cleavage of SREBPs

Rawson, Robert B.; Zelenski, Nikolai G.; Nijhawan, Deepak; Jin, Ye; Sakai, Juro; Hasan, Mazahir T.; Chang, Ta−Yuan; Brown, Michael S.; Goldstein, Joseph L.

doi:10.1016/s1097-2765(00)80006-4

Cited by 444 publications

(436 citation statements)

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“…M19 cells in which the orthologous Mbtps2 is deleted cannot grow in cholesterol and lipid-deficient culture media. 13 Wild-type MBTPS2 stably transfected into the M19 cells complemented this defect and restored their wild-type growth characteristics. None of the five mutants detected in IFAP patients retained this property to the same extent as did the wild-type gene; however, great variation was observed in residual activity.…”

Section: Discussionmentioning

confidence: 97%

“…[7][8][9][10][11][12] Oeffner et al 5 reported that IFAP syndrome is caused by functional deficiency of membrane-bound transcription factor protease, site 2, an intramembrane zinc metalloprotease that is essential for cholesterol homeostasis and the ER stress response. [13][14][15] They performed a linkage analysis involving two families of European descent, in which IFAP segregated according to an X-linked pattern of transmission, and assigned the IFAP locus to the 5.4-Mb region between DXS989 and DXS8019 on Xp22.11-p22.13. They identified five missense mutations exchanging highly conserved amino acids in MBTPS2 at Xp22.11 in five unrelated patients of European descent.…”

Section: Discussionmentioning

confidence: 99%

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A Japanese case of ichthyosis follicularis with atrichia and photophobia syndrome with an MBTPS2 mutation

et al. 2010

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Ichthyosis follicularis with atrichia and photophobia (IFAP) syndrome is a rare genetic disorder characterized by the triad of ichthyosis follicularis, alopecia and photophobia. Previous studies have identified five missense mutations in the membranebound transcription factor protease, site 2 (MBTPS2) gene in European patients with this syndrome. In this study, we detected the 1286G4A (Arg429His) mutation in MBTPS2 in a Japanese patient with IFAP syndrome. This mutation has previously been detected in a German family with this syndrome. Functional analysis revealed that this mutation was the most severe mutation identified to date for this syndrome. None of the male German patients had been tested for the mutation because they had several visceral and bone anomalies, and had died as neonates or infants. The clinical features of our 5-year-old patient are less severe than those of the German patients. Although he has neurological abnormalities, such as retarded psychomotor development and seizures, he does not have bone or visceral anomalies, except cryptorchidism. This case indicates the existence of other factor(s) that influence the clinical features of this syndrome. Further clinical and genetic studies are required to clarify the relationship between phenotypes and genotypes and to identify such modifying factors.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

A Japanese case of ichthyosis follicularis with atrichia and photophobia syndrome with an MBTPS2 mutation

et al. 2010

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“…Homologous signal peptide peptidases function in immunity by liberating signaling domains of TNFα and FasL (Fluhrer et al, 2006; Friedmann et al, 2006; Kirkin et al, 2007). Site-2 proteases are metalloenzymes that release transcription factors from the membrane to regulate membrane biogenesis and stress responses in diverse organisms from bacterial pathogens to man (Rawson et al, 1997; Makinoshima and Glickman, 2005). Lastly, rhomboid proteases act as prime regulators of signaling in insects by activating EGF signals through proteolytic shedding (Urban et al, 2001, 2002), and play prominent functions in diverse pathogen signaling and adhesion (Urban, 2009).…”

Section: Introductionmentioning

confidence: 99%

Membrane immersion allows rhomboid proteases to achieve specificity by reading transmembrane segment dynamics

Moin

Urban

2012

eLife

119

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Rhomboid proteases reside within cellular membranes, but the advantage of this unusual environment is unclear. We discovered membrane immersion allows substrates to be identified in a fundamentally-different way, based initially upon exposing ‘masked’ conformational dynamics of transmembrane segments rather than sequence-specific binding. EPR and CD spectroscopy revealed that the membrane restrains rhomboid gate and substrate conformation to limit proteolysis. True substrates evolved intrinsically-unstable transmembrane helices that both become unstructured when not supported by the membrane, and facilitate partitioning into the hydrophilic, active-site environment. Accordingly, manipulating substrate and gate dynamics in living cells shifted cleavage sites in a manner incompatible with extended sequence binding, but correlated with a membrane-and-helix-exit propensity scale. Moreover, cleavage of diverse non-substrates was provoked by single-residue changes that destabilize transmembrane helices. Membrane immersion thus bestows rhomboid proteases with the ability to identify substrates primarily based on reading their intrinsic transmembrane dynamics.DOI: http://dx.doi.org/10.7554/eLife.00173.001

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“…The M19 mutant of Chinese hamster ovary (CHO) cells is deficient in S2P (Hasan et al, 1994;Rawson et al, 1997). It was previously shown that M19 cells are unable to induce the expression of ERSE reporter gene or of the major ER chaperone BiP at either mRNA or protein levels in response to ER stress (Lee et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Analysis of ATF6 Activation in Site-2 Protease-deficient Chinese Hamster Ovary Cells

Nadanaka

Yoshida

Sato

et al. 2006

Cell Struct. Funct.

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ABSTRACT. Mammalian transcription factor ATF6 is constitutively synthesized as a type II transmembrane protein embedded in the endoplasmic reticulum (ER). It is activated when unfolded proteins are accumulated in the ER under ER stress through a process called regulated intramembrane proteolysis (Rip), in which ATF6 is transported from the ER to the Golgi apparatus where it undergoes sequential cleavage by Site-1 and Site-2 proteases. The cytosolic transcription factor domain of ATF6 liberated from the Golgi membrane enters the nucleus where it activates transcription of ER-localized molecular chaperones and folding enzymes, leading to the maintenance of the homeostasis of the ER. Here, we analyzed M19 cells, a mutant of Chinese hamster ovary cells deficient in Site-2 protease. It was previously shown that M19 cells are defective in the induction of mRNA encoding the major ER chaperone BiP. In M19 cells, ATF6 was not converted from the membrane-bound precursor form to the cleaved and nuclear form as expected. Moreover, some of the ATF6 was constitutively relocated to the Golgi apparatus, where it was cleaved by Site-1 protease, and remained associated with the Golgi apparatus, indicating that the ER of M19 cells was constitutively stressed. Consistent with this notion, the two other ER stress response mediators, IRE1 and PERK, were also constitutively activated in M19 cells. M19 cells showed inefficient secretion of a model protein. These results suggest that Rip-mediated activation of ATF6 is important for the homeostasis of the ER in not only ER-stressed but also unstressed cells.

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Complementation Cloning of , a Gene Encoding a Putative Metalloprotease Required for Intramembrane Cleavage of SREBPs

Cited by 444 publications

References 45 publications

A Japanese case of ichthyosis follicularis with atrichia and photophobia syndrome with an MBTPS2 mutation

A Japanese case of ichthyosis follicularis with atrichia and photophobia syndrome with an MBTPS2 mutation

Membrane immersion allows rhomboid proteases to achieve specificity by reading transmembrane segment dynamics

Analysis of ATF6 Activation in Site-2 Protease-deficient Chinese Hamster Ovary Cells

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