ArticleMolecular cell2024
Cleavage of the pseudoprotease iRhom2 by the signal peptidase complex reveals an ER-to-nucleus signaling pathway.
Article in Molecular cell, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 7 citations in OpenAlex.
- Transferrin receptor 1 shedding by the pro-inflammatory iRhom-ADAM17 complex and ADAM10 regulates cellular iron uptake and ferroptosis.Experimental & molecular medicine · 2026Article
- Structural basis of signal peptide recognition by the signal peptidase complex.Nature communications · 2026Article
- HTLV-1 p12 is cleaved to p8 by the signal peptidase complex and its inhibition impairs p8-dependent transmission.PLoS pathogens · 2025Article
- Endoplasmic reticulum homeostasis in plant-pathogen interactions: new scenarios for an old story.Journal of experimental botany · 2025Review
- 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.Cellular and molecular life sciences : CMLS · 2024Article
- Investigating iRHOM2-Associated Transcriptional Changes in Tylosis With Esophageal Cancer.Gastro hep advances · 2024Article
- Analysis of the function of ADAM17 in iRhom2 curly-bare and tylosis with esophageal cancer mutant mice.Journal of cell science · 2023Article
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.