iRHOM2: A Regulator of Palmoplantar Biology, Inflammation, and Viral Susceptibility

Abstract

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KOMPEITO, an Atypical Arabidopsis Rhomboid-Related Gene, Is Required for Callose Accumulation and Pollen Wall Development

“…Since the role of Rhomboid proteins was first demonstrated in the Drosophila EGF signaling pathway [ 46 , 53 ], the most characterized function of Rhomboid proteases conserved through organisms, including bacteria, animals and plants, is the proteolytic cleavage of membrane proteins [ 30 , 31 , 54 ]. Later, this family of proteins was implicated in diverse cellular processes, including protein homeostasis, viral susceptibility, mitochondria membrane fusion and parasite–host interaction [ 34 , 39 , 40 , 55 , 56 , 57 , 58 , 59 , 60 ]. The genetic and biochemical data presented in this study suggest that KOM acts not as a Rhomboid protease but as a member of the growing sub-family of proteolytically inactive Rhomboid-like proteins ( Supplementary Figure S3 ) [ 61 ].…”

S Protein, ACE2 and Host Cell Proteases in SARS-CoV-2 Cell Entry and Infectivity; Is Soluble ACE2 a Two Blade Sword? A Narrative Review

“…A proteolytically inactive rhomboid protein (iRhom2) encoded by Rhbdf2 gene involved in innate immunity against viral infections [ 165 ], regulates trafficking of pro-ADAM17 from endoplasmic reticulum to Golgi apparatus where furin detaches ADAM17 inhibitory prodomain to make it mature, substrate specific and be prepared for expression on the cell surface in complex with iRhom2 [ 166 , 167 ]. Infection with DNA and RNA viruses (influenza A, RSV) upregulates Rhbdf2 and ADAM17 genes [ 167 ]. However, an in vivo study revealed that ADAM17-dependent ectodomain shedding is a saturable phenomenon: it does not increase significantly when ADAM17 expression rises above a certain level [ 168 ].…”

Pathological mutations reveal the key role of the cytosolic iRhom2 N-terminus for phosphorylation-independent 14-3-3 interaction and ADAM17 binding, stability, and activity

“…List of used experiment IDs for indicated tissue and primary cells: a) murine heart: MM-00170 (Muchir et al, 2007), MM-00253 (Dufour et al, 2007), MM-00257 (Zhao et al, 2007), MM-00262 (Alcendor et al, 2007), MM-00300 (Ramchandran et al, 2006), MM-00322, (Thorrez et al, 2008), MM-00330 (Lattin et al, 2008), MM-00368 (Barger et al, 2008), MM-00384 (Wong et al, 2010), MM-00476 (Abd Alla et al, 2016), MM-00485 (Oka et al, 2011), MM-00492 (Wang et al, 2016), MM-00497 (Shuai et al, 2011), MM-00507 (Shuai et al, 2011), MM-00561 (Ricard et al, 2010), MM-00834 (Traister et al, 2013), MM-00841 (Mercader et al, 2012), MM-01538 (Gambino et al, 2013), MM-01642 (Lucas et al, 2014), MM-01875 (Lucas et al, 2014); b) murine primary fibroblast (dermis): MM-00159 (Vallender and Lahn, 2006), MM-00180 (Vallender and Lahn, 2006), MM-00627 (Garinis et al, 2009), MM-00724 (Garinis et al, 2009); c) murine primary keratinocytes: MM-01215 (Allende et al, 2013); d) healthy human epidermis tissue (biopsy): HS-02924 (Esaki et al, 2015); e) human primary keratinocytes (untreated): HS-02625 (Yunoki et al, 2018), HS-02787 (Busch et al, 2008), HS-02490 (Swindell et al, 2012), HS-00220 (Sa et al, 2007); f) human primary keratinocytes (treated with TNFα, IFNα, IFNγ or IL4; 24 h): HS-02490 (Swindell et al, 2012); g) human primary keratinocytes (treated with 10 ng/ml I IFNγ; 96 h): HS-02625 (Yunoki et al, 2018); h) human primary fibroblasts (untreated): HS-00393, HS-00481 (Chen et al, 2008), HS-00805 ...…”

“…The genetic disorder causing TOC is caused by single point mutations in the N-terminus (Howel-Evans et al, 1958, Ellis et al, 1994, Blaydon et al, 2012, Saarinen et al, 2012, Ellis et al, 2015, Mokoena et al, 2018). This disorder is characterised by symptoms such as leukoplakia and hyperkeratosis and increases the risk of OSCC (Chao-Chu et al, 2021). The mutations are classified as “gain of function” because they apparently upregulate ADAM17 activity, resulting in higher levels of EGFR ligands, EGFR hyperactivation in keratinocytes and increased release of TNF receptor 1, leading to reduced apoptosis (Blaydon et al, 2012, Maney et al, 2015, Hosur et al, 2018b).…”