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Cleavage of the pseudoprotease iRhom2 by the signal peptidase complex reveals an ER-to-nucleus signalling pathway
Cleavage of the pseudoprotease iRhom2 by the signal peptidase complex reveals an ER-to-nucleus signalling pathway
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Length:
20 minutes
Released:
Nov 29, 2022
Format:
Podcast episode
Description
Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2022.11.28.518246v1?rss=1
Authors: Dulloo, I., Tellier, M., Levet, C., Chikh, A., Zhang, B., Webb, C. M., Kelsell, D. P., Freeman, M.
Abstract:
iRhoms are pseudoprotease members of the rhomboid-like superfamily and are cardinal regulators of inflammatory and growth factor signalling; they function primarily by recognising transmembrane domains of their clients. Here we report an unexpected, and mechanistically distinct, nuclear function of iRhoms. iRhom2 is a non-canonical substrate of the 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 cellular transcriptome. We observed elevated nuclear iRhom2 in skin biopsies of patients with psoriasis and tylosis with oesophageal cancer (TOC); increased SPC-mediated iRhom2 cleavage in a psoriasis model; and overlapping transcriptional signatures between psoriasis and expression of the iRhom2 N-terminus. This work highlights the pathophysiological significance of this SPC-dependent ER-to-nucleus signalling pathway, and is the first example of a rhomboid-like protein that mediates protease-regulated nuclear signalling.
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Podcast created by Paper Player, LLC
http://biorxiv.org/cgi/content/short/2022.11.28.518246v1?rss=1
Authors: Dulloo, I., Tellier, M., Levet, C., Chikh, A., Zhang, B., Webb, C. M., Kelsell, D. P., Freeman, M.
Abstract:
iRhoms are pseudoprotease members of the rhomboid-like superfamily and are cardinal regulators of inflammatory and growth factor signalling; they function primarily by recognising transmembrane domains of their clients. Here we report an unexpected, and mechanistically distinct, nuclear function of iRhoms. iRhom2 is a non-canonical substrate of the 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 cellular transcriptome. We observed elevated nuclear iRhom2 in skin biopsies of patients with psoriasis and tylosis with oesophageal cancer (TOC); increased SPC-mediated iRhom2 cleavage in a psoriasis model; and overlapping transcriptional signatures between psoriasis and expression of the iRhom2 N-terminus. This work highlights the pathophysiological significance of this SPC-dependent ER-to-nucleus signalling pathway, and is the first example of a rhomboid-like protein that mediates protease-regulated nuclear signalling.
Copy rights belong to original authors. Visit the link for more info
Podcast created by Paper Player, LLC
Released:
Nov 29, 2022
Format:
Podcast episode
Titles in the series (100)
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