Journal
SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY
Volume 60, Issue -, Pages 29-37Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.semcdb.2016.06.022
Keywords
Rhomboid pseudoproteases; Endoplasmic reticulum-associated protein degradation; Vesicular trafficking control; Innate immunity; Cancer; Catalytically inactive enzyme homologs
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Funding
- Deutsche Forschungsgemeinschaft [SFB 1036]
- Marie Curie Career Integration Grant [PCIG13-GA-2013-618769]
- Worldwide Cancer Research [14-1289]
- Fundacao Calouste Gulbenkian
- Worldwide Cancer Research [14-1289] Funding Source: researchfish
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Rhomboids, proteases containing an unusual membrane-integral serine protease active site, were first identified in Drosophila, where they fulfill an essential role in epidermal growth factor receptor signaling, by cleaving membrane-tethered growth factor precursors. It has recently become apparent that eukaryotic genomes harbor conserved catalytically inactive rhomboid protease homologs, including derlins and iRhoms. Here we highlight how loss of proteolytic activity was followed in evolution by impressive functional diversification, enabling these pseudoproteases to fulfill crucial roles within the secretory pathway, including protein degradation, trafficking regulation, and inflammatory signaling. We distil the current understanding of the roles of rhomboid pseudoproteases in development and disease. Finally, we address mechanistically how versatile features of proteolytically active rhomboids have been elaborated to serve the sophisticated functions of their pseudoprotease cousins. By comparing functional and structural clues, we highlight common principles shared by the rhomboid superfamily, and make mechanistic predictions. (C) 2016 Elsevier Ltd. All rights reserved.
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