Abstract
The site-2 protease (S2P) is an unusually-hydrophobic integral membrane protease. It cleaves its substrates, which are membrane-bound transcription factors, within membrane-spanning helices. Although structural information for S2P from animals is lacking, the available data suggest that cleavage may occur at or within the lipid bilayer. In mammalian cells, S2P is essential owing to its activation of the sterol regulatory element binding proteins (SREBPs); in the absence of exogenous lipid, cells lacking S2P cannot survive. S2P is also important in the endoplasmic reticulum (ER) stress response, activating several different membrane-bound transcription factors. Human patients harboring reduction-of-function mutations in S2P exhibit an array of pathologies ranging from skin defects to neurological abnormalities. Surprisingly, Drosophila melanogaster lacking S2P are viable and fertile. This article is part of a Special Issue entitled: Intramembrane Proteases.
Keywords:
ER stress; Regulated intramembrane proteolysis; Rip; S2P; SREBP; Site-2 protease.
Copyright © 2013 Elsevier B.V. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Alopecia / enzymology
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Alopecia / genetics
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Alopecia / pathology
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Animals
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Drosophila melanogaster / enzymology
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Drosophila melanogaster / genetics
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Endoplasmic Reticulum Stress / genetics
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Genetic Diseases, X-Linked / enzymology
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Genetic Diseases, X-Linked / genetics
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Genetic Diseases, X-Linked / pathology
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Humans
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Ichthyosis / enzymology
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Ichthyosis / genetics
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Ichthyosis / pathology
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Lipid Metabolism
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Membrane Proteins / chemistry*
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Metalloendopeptidases / chemistry*
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Metalloendopeptidases / genetics
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Metalloendopeptidases / metabolism
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Mutation
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Photophobia / enzymology
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Photophobia / genetics
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Photophobia / pathology
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Signal Transduction*
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Skin Diseases, Genetic / enzymology
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Skin Diseases, Genetic / genetics
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Skin Diseases, Genetic / pathology
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Sterol Regulatory Element Binding Proteins / metabolism*
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Sterols / metabolism
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Substrate Specificity
Substances
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Membrane Proteins
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Sterol Regulatory Element Binding Proteins
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Sterols
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Metalloendopeptidases
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MBTPS2 protein, human
Supplementary concepts
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Ichthyosis follicularis atrichia photophobia syndrome
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Keratosis Follicularis Spinulosa Decalvans, X-Linked