<scp>iRhom1</scp> rescues cognitive dysfunction in multiple sclerosis via preventing myelin injury

Sun, Haolu; Yang, Hui; Wu, Yifei; Bian, He-ge; Wang, Menglin; Huang, Yan; Jin, Juan

doi:10.1111/gbb.12771

Cited by 3 publications

(2 citation statements)

References 35 publications

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“…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 nervous system ( Sun et al, 2021 ; Tüshaus et al, 2021 ) and in endothelial cells ( Babendreyer et al, 2020 ). iRhom2 KOs 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 diseases in mouse models ( Adrain et al, 2012 ; McIlwain et al, 2012 ; Siggs et al, 2012 ; Issuree et al, 2013 ; Luo et al, 2016 ; Barnette et al, 2018 ; Chaohui et al, 2018 ; Qing et al, 2018 ; Sundaram et al, 2019 ; Adrain & Cavadas, 2020 ; Kim et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

The ADAM17 sheddase complex regulator iTAP/Frmd8 modulates inflammation and tumor growth

et al. 2023

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The metalloprotease ADAM17 is a sheddase of key molecules, including TNF and epidermal growth factor receptor ligands. ADAM17 exists within an assemblage, the “sheddase complex,” containing a rhomboid pseudoprotease (iRhom1 or iRhom2). iRhoms control multiple aspects of ADAM17 biology. The FERM domain–containing protein iTAP/Frmd8 is an iRhom-binding protein that prevents the precocious shunting of ADAM17 and iRhom2 to lysosomes and their consequent degradation. As pathophysiological role(s) of iTAP/Frmd8 have not been addressed, we characterized the impact of iTAP/Frmd8 loss on ADAM17-associated phenotypes in mice. We show that iTAP/Frmd8 KO mice exhibit defects in inflammatory and intestinal epithelial barrier repair functions, but not the collateral defects associated with global ADAM17 loss. Furthermore, we show that iTAP/Frmd8 regulates cancer cell growth in a cell-autonomous manner and by modulating the tumor microenvironment. Our work suggests that pharmacological intervention at the level of iTAP/Frmd8 may be beneficial to target ADAM17 activity in specific compartments during chronic inflammatory diseases or cancer, while avoiding the collateral impact on the vital functions associated with the widespread inhibition of ADAM17.

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Section: Introductionmentioning

confidence: 99%

The ADAM17 sheddase complex regulator iTAP/Frmd8 modulates inflammation and tumor growth

et al. 2023

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Adrain

Badenes

Burbridge

et al. 2022

Preprint

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The metalloprotease ADAM17 catalyzes the shedding of key signalling molecules from the cell surface, including the inflammatory cytokine TNF (tumour necrosis factor) and activating ligands of the EGFR (epidermal growth factor receptor). ADAM17 exists within an assemblage called the "sheddase complex" containing a rhomboid pseudoprotease (iRhom1 or iRhom2). iRhoms control multiple aspects of ADAM17 biology, including its vesicular trafficking, maturation from its precursor pro-form, activation on the cell surface and specificity for subsets of proteolytic targets. Previous studies from our laboratory and others identified the FERM domain-containing protein Frmd8/iTAP as an iRhom-binding protein. iTAP is required to maintain the cell surface stability of the sheddase complex, thereby preventing the precocious shunting of ADAM17 and iRhom2 to lysosomes and their consequent degradation. As pathophysiological role(s) of iTAP have not been addressed, here we sought to characterize the impact of loss of iTAP on ADAM17-associated phenotypes in mice. Our data show that iTAP KO mice exhibit defects in ADAM17 activity in inflammatory and intestinal epithelial barrier repair functions, but do not exhibit the collateral effects associated with global loss of ADAM17. Furthermore, we show that iTAP promotes cancer cell growth in a cell-autonomous manner, and by modulating the tumor microenvironment. Our work suggests that pharmacological intervention at the level of iTAP may be beneficial to target ADAM17 activity in specific compartments during chronic inflammatory diseases or cancer, avoiding the deleterious impact on vital functions associated with the widespread inhibition of ADAM17 in normal tissues.

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GRP/GRPR signaling pathway aggravates hyperuricemia-induced renal inflammation and fibrosis via ABCG2-dependent mechanisms

Sun,

Bian,

Liu

et al. 2023

Biochemical Pharmacology

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iRhom1 rescues cognitive dysfunction in multiple sclerosis via preventing myelin injury

Cited by 3 publications

References 35 publications

The ADAM17 sheddase complex regulator iTAP/Frmd8 modulates inflammation and tumor growth

The ADAM17 sheddase complex regulator iTAP/Frmd8 modulates inflammation and tumor growth

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

GRP/GRPR signaling pathway aggravates hyperuricemia-induced renal inflammation and fibrosis via ABCG2-dependent mechanisms

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