SENP1 prevents steatohepatitis by suppressing RIPK1-driven apoptosis and inflammation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA796501 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17580300_1.fastq.gz | Fastqsanger.gz | |||
| SRR17580300_2.fastq.gz | Fastqsanger.gz | |||
| SRR17580303_1.fastq.gz | Fastqsanger.gz | |||
| SRR17580303_2.fastq.gz | Fastqsanger.gz | |||
| SRR17580306_1.fastq.gz | Fastqsanger.gz |
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Project description:The mechanism underlying RIPK1-driven cell death and inflammation, a key process in the progression of nonalcoholic steatohepatitis, remains unclear. Here we identified SENP1, a SUMO-specific protease, as a key endogenous inhibitor of RIPK1. SENP1 is progressively reduced in proportion to NASH severity in patients. Hepatocyte-specific SENP1-knockout mice develop spontaneous NASH-related phenotypes in a RIPK1 kinase-dependent manner. We demonstrate that SENP1 deficiency sensitizes cells to RIPK1 kinase-dependent apoptosis by promoting RIPK1 activation following TNFα stimulation. Mechanistically, SENP1 deSUMOylates RIPK1 in TNF-R1 signaling complex (TNF-RSC), keeping RIPK1 in check. Loss of SENP1 leads to SUMOylation of RIPK1, which re-orchestrates TNF-RSC and modulates the ubiquitination patterns and activity of RIPK1. Notably, genetic inhibition of RIPK1 effectively reverses disease progression in hepatocyte-specific SENP1-knockout male mice with high-fat-diet-induced nonalcoholic fatty liver. We propose that deSUMOylation of RIPK1 by SENP1 provides a pathophysiologically relevant cell death-restricting checkpoint that modulates RIPK1 activation in the pathogenesis of nonalcoholic steatohepatitis.
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Project description:SENP1 deSUMOylates RIPK1 in TNF-R1 signaling complex (TNF-RSC), keeping RIPK1 in check. Loss of SENP1 leads to SUMOylation of RIPK1, which re-orchestrates TNF-RSC and modulates the ubiquitination patterns and activity of RIPK1.
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Project description:Activation of RIPK1-driven cell death and inflammation play important roles in the progression of nonalcoholic steatohepatitis (NASH). However, the mechanism underlying RIPK1 activation in NASH remains unclear. Here we identified SENP1, a SUMO-specific protease, as a key endogenous inhibitor of RIPK1. SENP1 is progressively reduced in proportion to NASH severity in patients. Hepatocyte-specific SENP1-knockout mice develop spontaneous NASH-related phenotypes in a RIPK1 kinase-dependent manner. We demonstrate that SENP1 deficiency sensitizes cells to RIPK1 kinase-dependent apoptosis by promoting RIPK1 activation following TNFα stimulation. Mechanistically, SENP1 deSUMOylates RIPK1 in TNF-R1 signaling complex (TNF-RSC), keeping RIPK1 in check. Loss of SENP1 leads to SUMOylation of RIPK1, which re-orchestrates TNF-RSC and modulates the ubiquitination patterns and activity of RIPK1. Notably, genetic inhibition of RIPK1 effectively reverses disease progression in hepatocyte-specific SENP1-knockout male mice with high-fat-diet-induced nonalcoholic fatty liver. We propose that deSUMOylation of RIPK1 by SENP1 provides a pathophysiologically relevant cell death-restricting checkpoint that modulates RIPK1 activation in the pathogenesis of nonalcoholic steatohepatitis.
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Project description:Aging is a major risk factor for both genetic and sporadic neurodegenerative disorders. However, it is unclear how aging interacts with genetic predispositions to promote neurodegeneration. Here we investigate how partial loss-of-function of TBK1, a major genetic cause for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comorbidity, leads to age-dependent neurodegeneration. We show that TBK1 is an endogenous inhibitor of RIPK1 and the embryonic lethality of Tbk1-/- mice is dependent on RIPK1 kinase activity. In aging human brains, another endogenous RIPK1 inhibitor, TAK1, exhibits a marked decrease in expression. We show that in Tbk1+/- mice, the reduced myeloid TAK1 expression promotes all the key hallmarks of ALS/FTD, including neuroinflammation, TDP-43 aggregation, axonal degeneration, neuronal loss and behavior deficits, which are blocked upon inhibition of RIPK1. Thus, aging facilitates RIPK1 activation by reducing TAK1 expression, which cooperates with genetic risk factors to promote the onset of ALS/FTD.
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