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SPATA2 restricts OTULIN-dependent LUBAC activity independently of CYLD

Griewahn, Laura ; Müller, Madeleine ; Peintner, Lukas ; Wissler, Manuela ; Weiss, Martina ; Brauns-Schubert, Prisca ; Massoumi, Ramin LU ; Borner, Christoph ; Groß, Olaf and Yabal, Monica , et al. (2023) In Cell Reports 42(1).
Abstract

SPATA2 mediates the recruitment of CYLD to immune receptor complexes by bridging the interaction of CYLD with the linear ubiquitylation assembly complex (LUBAC) component HOIP. Whether SPATA2 exhibits functions independently of CYLD is unclear. Here, we show that, while Cyld−/− and Spata2−/− mice are viable, double mutants exhibit highly penetrant perinatal lethality, indicating independent functions of SPATA2 and CYLD. Cyld−/−Spata2−/− fibroblasts show increased M1-linked TNFR1-SC ubiquitylation and, similar to Cyld−/−Spata2−/− macrophages and intestinal epithelial cells, elevated pro-inflammatory gene expression compared with Cyld−/− or Spata2−/−... (More)

SPATA2 mediates the recruitment of CYLD to immune receptor complexes by bridging the interaction of CYLD with the linear ubiquitylation assembly complex (LUBAC) component HOIP. Whether SPATA2 exhibits functions independently of CYLD is unclear. Here, we show that, while Cyld−/− and Spata2−/− mice are viable, double mutants exhibit highly penetrant perinatal lethality, indicating independent functions of SPATA2 and CYLD. Cyld−/−Spata2−/− fibroblasts show increased M1-linked TNFR1-SC ubiquitylation and, similar to Cyld−/−Spata2−/− macrophages and intestinal epithelial cells, elevated pro-inflammatory gene expression compared with Cyld−/− or Spata2−/− cells. We show that SPATA2 competes with OTULIN for binding to HOIP via its PUB-interacting motif (PIM) and its zinc finger domain, thereby promoting autoubiquitylation of LUBAC. Consistently, increased pro-inflammatory signaling in Cyld−/−Spata2−/− cells depends on the presence of OTULIN. Our data therefore indicate that SPATA2 counteracts, independently of CYLD, the deubiquitylation of LUBAC by OTULIN and thereby attenuates LUBAC activity and pro-inflammatory signaling.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
apoptosis, cell death, CP: Immunology, CP: Molecular biology, CYLD, inflammation, LUBAC, OTULIN, SPATA2, ubiquitylation
in
Cell Reports
volume
42
issue
1
article number
111961
publisher
Cell Press
external identifiers
  • scopus:85147102946
  • pmid:36640323
ISSN
2211-1247
DOI
10.1016/j.celrep.2022.111961
language
English
LU publication?
yes
id
71188e22-1bd7-438c-8f73-8c366f1cd6e5
date added to LUP
2023-02-10 15:34:06
date last changed
2024-06-13 04:40:19
@article{71188e22-1bd7-438c-8f73-8c366f1cd6e5,
  abstract     = {{<p>SPATA2 mediates the recruitment of CYLD to immune receptor complexes by bridging the interaction of CYLD with the linear ubiquitylation assembly complex (LUBAC) component HOIP. Whether SPATA2 exhibits functions independently of CYLD is unclear. Here, we show that, while Cyld<sup>−/−</sup> and Spata2<sup>−/−</sup> mice are viable, double mutants exhibit highly penetrant perinatal lethality, indicating independent functions of SPATA2 and CYLD. Cyld<sup>−/−</sup>Spata2<sup>−/−</sup> fibroblasts show increased M1-linked TNFR1-SC ubiquitylation and, similar to Cyld<sup>−/−</sup>Spata2<sup>−/−</sup> macrophages and intestinal epithelial cells, elevated pro-inflammatory gene expression compared with Cyld<sup>−/−</sup> or Spata2<sup>−/−</sup> cells. We show that SPATA2 competes with OTULIN for binding to HOIP via its PUB-interacting motif (PIM) and its zinc finger domain, thereby promoting autoubiquitylation of LUBAC. Consistently, increased pro-inflammatory signaling in Cyld<sup>−/−</sup>Spata2<sup>−/−</sup> cells depends on the presence of OTULIN. Our data therefore indicate that SPATA2 counteracts, independently of CYLD, the deubiquitylation of LUBAC by OTULIN and thereby attenuates LUBAC activity and pro-inflammatory signaling.</p>}},
  author       = {{Griewahn, Laura and Müller, Madeleine and Peintner, Lukas and Wissler, Manuela and Weiss, Martina and Brauns-Schubert, Prisca and Massoumi, Ramin and Borner, Christoph and Groß, Olaf and Yabal, Monica and Charvet, Céline and Maurer, Ulrich}},
  issn         = {{2211-1247}},
  keywords     = {{apoptosis; cell death; CP: Immunology; CP: Molecular biology; CYLD; inflammation; LUBAC; OTULIN; SPATA2; ubiquitylation}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Cell Press}},
  series       = {{Cell Reports}},
  title        = {{SPATA2 restricts OTULIN-dependent LUBAC activity independently of CYLD}},
  url          = {{http://dx.doi.org/10.1016/j.celrep.2022.111961}},
  doi          = {{10.1016/j.celrep.2022.111961}},
  volume       = {{42}},
  year         = {{2023}},
}