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Cleavage of the pseudoprotease iRhom2 by the signal peptidase complex reveals an ER-to-nucleus signalling pathway

ABSTRACT: iRhoms are pseudoprotease members of the rhomboid-like superfamily and are cardinal regulators of inflammatory and growth factor signaling; they function primarily by recognizing transmembrane domains of their clients. Here, we report a mechanistically distinct nuclear function of iRhoms, showing that both human and mouse iRhom2 are non-canonical substrates of signal peptidase complex (SPC), the protease that removes signal peptides from secreted proteins. Cleavage of iRhom2 generates an N-terminal fragment that enters the nucleus and modifies the transcriptome, in part by binding C-terminal binding proteins (CtBPs). The biological significance of nuclear iRhom2 is indicated by elevated levels in skin biopsies of patients with psoriasis, tylosis with oesophageal cancer (TOC), and non-epidermolytic palmoplantar keratoderma (NEPPK); increased iRhom2 cleavage in a keratinocyte model of psoriasis; and nuclear iRhom2 promoting proliferation of keratinocytes. Overall, this work identifies an unexpected SPC-dependent ER-to-nucleus signaling pathway and demonstrates that iRhoms can mediate nuclear signaling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE219008 | GEO | 2024/01/04

REPOSITORIES: GEO

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Congenital iRHOM2 deficiency causes ADAM17 dysfunction and environmentally directed immunodysregulatory disease [whole blood]

Project description:We report a pleiotropic disease due to loss-of-function mutations in RHBDF2, the gene encoding iRHOM2, in 2 kindreds with recurrent infections in different organs. One patient had recurrent pneumonia but no colon involvement, another had recurrent infectious hemorrhagic colitis but no lung involvement, and the other two experienced recurrent respiratory infections. Loss of iRHOM2, a rhomboid superfamily member that regulates the ADAM17 metalloproteinase, caused defective ADAM17-dependent cleavage and release of cytokines, including TNF and amphiregulin. To understand the diverse clinical phenotypes, we challenged Rhbdf2-/- mice with Pseudomonas aeruginosa by nasal gavage and observed more severe pneumonia whereas infection with Citrobacter rodentium caused worse inflammatory colitis than wild-type mice. The fecal microbiota in the colitis patient had characteristic oral species that can predispose to colitis. Thus, a new human immunodeficiency arising from iRHOM2 deficiency causes divergent disease phenotypes that can involve the local microbial environment.

2021-11-03 | GSE184876 | GEO

Congenital iRHOM2 deficiency causes ADAM17 dysfunction and environmentally directed immunodysregulatory disease [T cells]

2021-11-03 | GSE184875 | GEO

iRhom2 Promotes Lupus Nephritis through ADAM17-Dependent TNF-α and EGFR Signaling

Project description:Lupus nephritis (LN) often results in progressive renal dysfunction. The inactive Rhomboid 2 (iRhom2) is a newly identified key regulator of A disintegrin and metalloprotease 17 (ADAM17), whose substrates, such as TNF-α and heparin-binding EGF (HB-EGF), have been implicated in the pathogenesis of chronic kidney disease. Here we demonstrate that deficiency of iRhom2 protects the lupus-prone Fcgr2b-/- mice from developing severe kidney damage without altering anti-double stranded (ds) DNA Ab production, by simultaneously blocking the HB-EGF/EGFR and the TNF-α signaling in the kidney tissues. Unbiased transcriptome profiling of kidneys and kidney macrophages revealed that TNF-α and HB-EGF/EGFR signaling pathways are highly upregulated in Fcgr2b-/- mice; alterations that were diminished in the absence of iRhom2. Pharmacological blockade of either TNF-α or EGFR signaling protected Fcgr2b-/- mice from severe renal damage. Finally, kidneys from LN patients showed increased iRhom2 and HB-EGF expression, with interstitial HB-EGF expression significantly associated with chronicity indices. Our data suggest that activation of iRhom2/ADAM17-dependent TNF-α and EGFR signaling plays a crucial role in mediating irreversible kidney damage in LN, thereby uncovering a novel target for selective and simultaneous dual inhibition of two major pathological pathways in the effector arm of the disease.

2019-01-01 | GSE107705 | GEO

Phosphorylation of iRhom2 controls stimulated proteolytic shedding by the metalloprotease ADAM17/TACE

Project description:TACE (TNFa Converting Enzyme), is responsible for cleavage (‘shedding’) of membrane-tethered signaling molecules such as TNF of EGFR ligands. TACE interacts with iRhom2, which mediates the exit of TACE from the endoplasmic reticulum. In this study we analyze a new role for iRHOM2, where a fraction of the protein remains in the membrane and the phosphorylation of different residues in its cytoplasmatic tail is necessary for TACE shedding function.

2021-11-03 | PXD007763 | Pride

Structure of the human signal peptidase complex

Project description:The ER-resident signal peptidase complex (SPC) is an essential membrane protein complex involved in the maturation of soluble and type-I transmembrane proteins destined to the secretory pathway. As a part of the ER translocon machinery, the SPC removes signal peptides (SPs) from the N-termini of many proteins such as hormones, antibodies, or secretory enzymes1,2. To accomplish this task, the SPC must process a large variety of SPs with an exquisite specificity. Although the determinants of SP recognition have been established empirically3, the molecular details of SP recognition and removal remain elusive. Here, we show that the human SPC exists in two functional paralogs with distinct proteolytic subunits. We determined the structures and posttranslational modifications of both paralogs using electron cryo-microscopy and structural proteomics. The respective proteolytic subunits SEC11A and SEC11C adopt a conserved signal peptidase (SPase) fold with their active sites facing a prominent transmembrane window, which is collectively formed by the transmembrane domains of all SPC subunits. Characteristic, charged regions on both sides of this window locally thin the membrane by approximately 40% compared to the exterior. The data suggest a mechanistic model for SPC specificity and the transfer of SPs from the Sec61 translocation channel to the SPC.

2021-07-05 | PXD022002 | Pride

iRHOM2 deficiency causes environmentally directed immunodysregulatory disease

Project description:iRHOM2 deficiency causes environmentally directed immunodysregulatory disease

| PRJNA741289 | ENA

iRHOM2 deficiency causes environmentally directed immunodysregulatory disease

Project description:iRHOM2 deficiency causes environmentally directed immunodysregulatory disease

| PRJNA741290 | ENA

Identification of candidate interactors of Bacillus subtilis rhomboid protease YqgP

Project description:Magnesium homeostasis is essential for life and depends on magnesium transporters whose activity and ion selectivity needs to be tightly controlled. Rhomboid intramembrane proteases pervade the prokaryotic kingdom but their functions are largely elusive. Using proteomics we find that Bacillus subtilis rhomboid protease YqgP interacts with the membrane bound ATP-dependent processive metalloprotease FtsH and cleaves MgtE, the major high-affinity magnesium transporter in B. subtilis. MgtE cleavage by YqgP is potentiated in low magnesium and high manganese or zinc conditions, which protects B. subtilis from Mn2+/ Zn2+ toxicity. The N-terminal cytosolic domain of YqgP binds Mn2+ and Zn2+ and facilitates MgtE cleavage. Independently of its protease activity, YqgP acts as a substrate adaptor for FtsH, which is necessary for degradation of MgtE. YqgP thus unites a protease and pseudoprotease function, which indicates the evolutionary origin of rhomboid pseudoproteases, such as Derlins that are intimately involved in ER associated degradation. Conceptually, the YqgP-FtsH system we describe here is equivalent to a primordial form of ‘ERAD’ in bacteria and exemplifies an ancestral function of rhomboid-superfamily proteins.

2020-01-09 | PXD014566 | Pride

Rhomboid mediates membrane protein quality control as an intramembrane protease and adaptor of AAA protease.

Project description:Magnesium homeostasis is essential for life and depends on magnesium transporters whose activity and ion selectivity need to be tightly controlled. Rhomboid intramembrane proteases pervade the prokaryotic kingdom but their functions are largely elusive. Using proteomics we find that Bacillus subtilis rhomboid protease YqgP interacts with the membrane bound ATP-dependent processive metalloprotease FtsH and cleaves MgtE, the major high-affinity magnesium transporter in B. subtilis. MgtE cleavage by YqgP is potentiated in low magnesium and high manganese or zinc conditions, which protects B. subtilis from Mn2+/ Zn2+ toxicity. The N-terminal cytosolic domain of YqgP binds Mn2+ and Zn2+ and facilitates MgtE cleavage. Independently of its protease activity, YqgP acts as a substrate adaptor for FtsH, which is necessary for degradation of MgtE. YqgP thus unites a protease and pseudoprotease function, which indicates the evolutionary origin of rhomboid pseudoproteases, such as Derlins that are intimately involved in ER associated degradation. Conceptually, the YqgP-FtsH system we describe here is equivalent to a primordial form of ‘ERAD’ in bacteria and exemplifies an ancestral function of rhomboid-superfamily proteins.

2020-01-09 | PXD014578 | Pride

ZNF750 in late keratinocyte differentiation

Project description:Disrupted skin barrier due to altered keratinocyte differentiation is common in pathologic conditions such as atopic dermatitis, ichthyosis and psoriasis. However, the molecular cascades governing keratinocyte terminal differentiation are still poorly understood. We have previously demostrated that a dominante mutation in ZNF750 leads to a clinical phenotype that reminiscent of psoriasis and seborrehic dermatitis. We defined ZNF750 as a nuclear effector that is atrongly activated in and essiential for keratinocyte terminal differentiation. ZNF750 knockdown in HaCaT keratinocytes markedly reduced the expression of epidermal late differentiation markers, including gene subsets of epidermal differentiation complex and skin barrier formation such as FLG, LOR, SPINK5, ALOX12B and DSG1, known to be mutated in various human skin diseases. Furthermore, ZNF750 over-expression in undifferentiated cells induced terminal differentiation genes. Thus, ZNF750 is a regulator of keratinocyte terminal differnetiation, and with its downstream targets can serve in future elucidation of therapeutics for common disease of skin barrier Gene expression analysis: To determine the differentaition signature for HaCaT keratinocytes, with ZNF750 gene silencing, total RNA was isolated in biologic triplicates from cells induced to differentiate for twelve days and hybridized to Affymerix Human Gene 1.0 ST arrays.

2012-09-24 | E-GEOD-38039 | biostudies-arrayexpress

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