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

Journal article

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

Authors: Dulloo, I; Tellier, M; Levet, C; Chikh, A; Zhang, B

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cell Press
• Journal: Molecular Cell
• Volume: 84
• Issue: 2
• Pages: 277-292.e9
• Publication date: 2024-01-05
• DOI: 10.1016/j.molcel.2023.12.012
• EISSN: 1097-4164
• ISSN: 1097-2765
• Language: English
• Keywords: Nuclear localization sequence; Nuclear protein; Cell culture; Transcription factor; Gene; Cell biology; Cleavage (geology); Receptor; Signal transduction; Genetics; Keratinocyte; Nucleus; Transmembrane protein; Cell nucleus; Biology