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

Lemberg, Marius K; Adrain, Colin

http://hdl.handle.net/10400.7/759

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Authors

Lemberg, Marius K

Adrain, Colin

Abstract(s)

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.

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Keywords

Rhomboid pseudoproteases Endoplasmic reticulum-associated protein degradation Vesicular trafficking control Vesicular trafficking control Cancer Catalytically inactive enzyme homologs

URI

http://hdl.handle.net/10400.7/759

Citation

Marius K. Lemberg, Colin Adrain, Inactive rhomboid proteins: New mechanisms with implications in health and disease, Seminars in Cell & Developmental Biology, Volume 60, December 2016, Pages 29-37, ISSN 1084-9521, https://doi.org/10.1016/j.semcdb.2016.06.022. (http://www.sciencedirect.com/science/article/pii/S1084952116301847) Keywords: Rhomboid pseudoproteases; Endoplasmic reticulum-associated protein degradation; Vesicular trafficking control; Innate immunity; Cancer; Catalytically inactive enzyme homologs