The complex life of rhomboid pseudoproteases

Abstract

Rhomboid pseudoproteases are catalytically inactive members of the rhomboid superfamily. The founding members, rhomboids, were first identified in Drosophila as serine intramembrane proteases that cleave transmembrane proteins, enabling signaling. This led to the discovery of the wider rhomboid superfamily, a clan that in metazoans is dominated by pseudoproteases. These so-called rhomboid pseudoproteases inherited from their catalytically active ancestors a conserved rhomboid-like domain and a propensity to regulate signaling. Lacking catalytic activity, they developed new 'pseudoenzyme' functions that include regulating the trafficking, turnover, and activity of their client proteins. Rhomboid pseudoproteases have preeminent roles in orchestrating immune cell activation, antiviral responses, and cytokine release in response to microbial infection, or in chronic diseases, and have also been implicated in growth factor signaling, cancer, and, more recently, metabolism. Here, we discuss the mechanism(s) of action of rhomboid pseudoproteases, contrasted with rhomboid proteases. We also highlight the roles of rhomboid pseudoproteases in mammalian physiology, which, quite paradoxically among pseudoenzymes, is understood much better than active rhomboids.

RHBDD2‑WWOX protein interaction during proliferative and differentiated stages in normal and breast cancer cells

“…Regarding the mammary gland, increased Rhbdd2 expression is associated with the pregnancy stage (11). RHBDD2 encodes one of nine known rhomboid pseudoproteases whose functional roles are defined by binding to target proteins (2). Recently, RHBDD2 was detected among multiple WWOX protein interactors under physiological conditions using a proteomic scale approach (12).…”

“…Rhomboid pseudoproteases lack catalytic activity and are primarily located in the endoplasmic reticulum (ER) and Golgi apparatus (3). The functional role of these pseudoproteases includes the ability to recognize and recruit target proteins to regulate their subcellular fate, turnover and degradation, affecting various signaling pathways and pathophysiological processes (2). A number of rhomboid pseudoproteases are associated with neoplastic disease (including iRhom1, iRhom2 and Derlin1) via activation of diverse cancer signaling pathways, such as WNT, HIF-1, VEGF and EGFR signaling (4)(5)(6)(7).…”

The ADAM17 sheddase complex regulator iTAP modulates inflammation, epithelial repair, and tumor growth

“…Over the past 10 years, significant knowledge has emerged concerning how ADAM17 is regulated at the biochemical, cell biological and organismal levels. We and others discovered that certain pseudoenzymes called iRhoms are essential cofactors for ADAM17; without iRhoms ADAM17 is proteolytically inactive and hence ADAM17 substrate shedding is abolished (Adrain et al ., 2012; McIlwain et al ., 2012; Siggs et al ., 2012; Li et al ., 2015) (Adrain and Cavadas, 2020). Mammals encode two iRhom paralogs with partially redundant roles in ADAM17 regulation at the organismal and cellular levels (Christova et al ., 2013; Li et al ., 2015).…”

“…iRhom1 regulates ADAM17 shedding in the brain(Sun et al ., 2021), nervous system (Tüshaus et al ., 2021) and in endothelial cells (Babendreyer et al ., 2020). iRhom2 KO which develop normally but fail to secrete TNF, a key ADAM17 substrate that coordinates the responses to infection and chronic inflammatory diseases; loss of iRhom2 attenuates the development of multiple inflammatory disease models in mice (Adrain et al ., 2012; McIlwain et al ., 2012; Siggs et al ., 2012; Adrain and Cavadas, 2020) (Barnette et al ., 2018) (Kim et al ., 2020) (Issuree et al ., 2013; Luo et al ., 2016; Chaohui et al ., 2018; Qing et al ., 2018; Sundaram et al ., 2019). By contrast, the double KO of iRhom1 and iRhom2 in mice results in embryonic or perinatal lethality (Christova et al ., 2013; Li et al ., 2015).…”

“…phorbol esters, inflammatory stimuli), the cytoplasmic tail of iRhom proteins undergo phosphorylation, which drives the recruitment of 14-3- 3 proteins to this domain of iRhom (Cavadas et al ., 2017; Grieve et al ., 2017). This event triggers the activation of ADAM17, potentially driven by triggering a molecular rearrangement of the complex or displacing ADAM17 from the sheddase complex (Adrain and Cavadas, 2020).…”