Inactive rhomboid proteins: New mechanisms with implications in health and disease

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• 作者：Marius K. Lemberg^a ; ^{m.lemberg@zmbh.uni-heidelberg.de} ; Colin Adrain^b ; ^{cadrain@igc.gulbenkian.pt}
• 关键词：ADAM17 ; a disintegrin and metalloproteinase 17 ; COG ; conserved oligomeric Golgi ; Der1 ; degradation in the ER 1 ; Dfm1 ; Der1-like family member 1 ; DKO ; double knockout ; EGFR ; epidermal growth factor receptor ; ER ; endoplasmic reticulum ; ERAD ; ER-associated degradation ; ERAD-R ; regulatory ERAD ; IRHD ; iRhom homology domain ; iRhom ; inactive rhomboid ; KO ; knockout ; L1 ; loop 1 ; RHBDD ; rhomboid domain-containing ; RHBDL ; rhomboid-like protein ; SELMA ; symbiont specific ERAD-like machinery ; SPP ; signal pept
• 刊名：Seminars in Cell & Developmental Biology
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：60
• 期：Complete
• 页码：29-37
• 全文大小：1789 K
• 卷排序：60

文摘

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.