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OTULIN limits cell death and inflammation by deubiquitinating LUBAC
Klaus Heger1, Katherine E Wickliffe1, Ada Ndoja1
1Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA.
Nature
|June 29, 2018
Summary
OTULIN protein prevents self-ubiquitination of LUBAC, a complex critical for preventing inflammation and embryonic lethality. Loss of OTULIN function leads to cell death and type I interferon production.
Area of Science:
- Cellular biology
- Immunology
- Molecular biology
Background:
- OTULIN (OTU deubiquitinase with linear linkage specificity) removes linear polyubiquitin from LUBAC (linear ubiquitin chain assembly complex) substrates.
- OTULIN is crucial for preventing auto-inflammatory diseases and embryonic lethality.
Purpose of the Study:
- To investigate the precise role of OTULIN in regulating LUBAC activity and its downstream consequences.
- To elucidate the mechanisms by which OTULIN deficiency leads to embryonic lethality and auto-inflammation.
Main Methods:
- Generation of knock-in mice expressing catalytically inactive OTULIN.
- Analysis of cell death pathways (TNFR1, RIPK1, caspase 8, RIPK3) in OTULIN-deficient models.
- Assessment of type I interferon production in mutant mice.
Main Results:
- Catalytically inactive OTULIN phenocopies LUBAC deficiency, causing midgestation embryonic lethality due to TNFR1/RIPK1-mediated cell death.
- Inactivation of OTULIN in adult mice triggers pro-inflammatory cell death, which is rescued by combined loss of caspase 8 and RIPK3.
- OTULIN mutant mice lacking caspase 8 and RIPK3 exhibit perinatal lethality with enhanced RIPK1-dependent type I interferon production.
Conclusions:
- OTULIN and LUBAC function in a linear pathway, with OTULIN promoting LUBAC activity by preventing its auto-ubiquitination.
- OTULIN plays a critical role in regulating cell death pathways and type I interferon induction.
- These findings reveal a novel link between linear ubiquitination, cell death, and innate immune responses.
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