TRIM28 SUMOylates and stabilizes NLRP3 to facilitate inflammasome activation

Qin, Ying; Li, Qi; Liang, Wenbo; Yan, Rongzhen; Li, Tong; Jia, Mutian; Zhao, Chenyang; Zhao, Wei

doi:10.1038/s41467-021-25033-4

Cited by 72 publications

(40 citation statements)

References 35 publications

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“…Interestingly, SENP3 action has a negative effect on speck formation and inflammasome activation in contrast to what SENP6 and SENP7 function ( Shao et al, 2020 ). Aligned with UBC9 data, Qin et al (2021) have described that E3 SUMO ligase tripartite motif-containing protein 28 (TRIM28) is an enhancer of NLRP3 inflammasome activation by facilitating NLRP3 expression. TRIM28 binds NLRP3, promotes SUMO1, SUMO2, and SUMO3 modification of NLRP3, and impairs NLRP3 ubiquitination degradation via proteasome.…”

Section: Inflammasome Components Sumoylationmentioning

confidence: 98%

Posttranslational Regulation of Inflammasomes, Its Potential as Biomarkers and in the Identification of Novel Drugs Targets

Nanda

Vollmer²,

Pérez-Oliva

2022

Front. Cell Dev. Biol.

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In this review, we have summarized classical post-translational modifications (PTMs) such as phosphorylation, ubiquitylation, and SUMOylation of the different components of one of the most studied NLRP3, and other emerging inflammasomes. We will highlight how the discovery of these modifications have provided mechanistic insight into the biology, function, and regulation of these multiprotein complexes not only in the context of the innate immune system but also in adaptive immunity, hematopoiesis, bone marrow transplantation, as well and their role in human diseases. We have also collected available information concerning less-studied modifications such as acetylation, ADP-ribosylation, nitrosylation, prenylation, citrullination, and emphasized their relevance in the regulation of inflammasome complex formation. We have described disease-associated mutations affecting PTMs of inflammasome components. Finally, we have discussed how a deeper understanding of different PTMs can help the development of biomarkers and identification of novel drug targets to treat diseases caused by the malfunctioning of inflammasomes.

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Section: Inflammasome Components Sumoylationmentioning

confidence: 98%

Posttranslational Regulation of Inflammasomes, Its Potential as Biomarkers and in the Identification of Novel Drugs Targets

Nanda

Vollmer²,

Pérez-Oliva

2022

Front. Cell Dev. Biol.

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“…In addition to regulating a diverse set of viruses, KAP1 has been implicated in a variety of host biological processes including innate immunity, tumor microenvironment regulation, and immune cell development, among others ( Czerwinska et al., 2020 ; Lee et al., 2020 ; Liang et al., 2020 ; Liu et al., 2020 ; Chikuma et al, 2021 ; Park et al., 2021 ) ( Figure 3 ). While some of these reported KAP1-dependent functions are mediated by KAP1 repression of ERVs ( Tie et al., 2018 ; Schmidt et al., 2019 ; Lee et al., 2020 ), many of these cellular roles have been mediated by KAP1 regulating transcription of host genes ( Kamitani et al., 2008 ; Wang et al., 2017 ) or through KAP1 utilizing its E3 ubiquitin ligase function to degrade specific factors ( Liang et al., 2011 ; Qin et al., 2021 ).…”

Section: Kap1 Regulation Of Cell Fate Responses and Immune Cell Funct...mentioning

confidence: 99%

KAP1/TRIM28: Transcriptional Activator and/or Repressor of Viral and Cellular Programs?

Randolph

Hyder

D’Orso

2022

Front. Cell. Infect. Microbiol.

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Several transcriptional and epigenetic regulators have been functionally linked to the control of viral and cellular gene expression programs. One such regulator is Krüppel-associated box (KRAB)-associated protein 1 (KAP1: also named TRIM28 or TIF1β), which has been extensively studied in the past three decades. Here we offer an up-to date review of its various functions in a diversity of contexts. We first summarize the discovery of KAP1 repression of endogenous retroviruses during development. We then deliberate evidence in the literature suggesting KAP1 is both an activator and repressor of HIV-1 transcription and discuss experimental differences and limitations of previous studies. Finally, we discuss KAP1 regulation of DNA and RNA viruses, and then expand on KAP1 control of cellular responses and immune functions. While KAP1 positive and negative regulation of viral and cellular transcriptional programs is vastly documented, our mechanistic understanding remains narrow. We thus propose that precision genetic tools to reveal direct KAP1 functions in gene regulation will be required to not only illuminate new biology but also provide the foundation to translate the basic discoveries from the bench to the clinics.

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“…Interestingly, inflammasome activation tends to upregulate NO generation suggesting an autoregulatory mechanism (Yang et al, 2017). Recent studies have demonstrated that SUMOylation of NLRP3 by UBC9-directed SUMO1 and TRIM28-directed SUMO1-3 are important for inflammasome activation and that de-SUMOylation by the SUMO-specific protease SENP3 can reduce inflammasome activation (Shao et al, 2020;Qin et al, 2021). ADP-ribosylation of NLRP3 by the Mycoplasma pneumoniae CARDS-toxin can trigger inflammasome activation for a robust inflammatory response (Bose et al, 2014).…”

Section: Other Post-translational Modificationsmentioning

confidence: 99%

Crosstalk Between the NLRP3 Inflammasome/ASC Speck and Amyloid Protein Aggregates Drives Disease Progression in Alzheimer’s and Parkinson’s Disease

Hulse

Bhaskar

2022

Front. Mol. Neurosci.

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Two key pathological hallmarks of neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), are the accumulation of misfolded protein aggregates and the chronic progressive neuroinflammation that they trigger. Numerous original research and reviews have provided a comprehensive understanding of how aggregated proteins (amyloid β, pathological tau, and α-synuclein) contribute to the disease, including driving sterile inflammation, in part, through the aggregation of multi-protein inflammasome complexes and the ASC speck [composed of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), Apoptosis-associated speck-like protein containing a C-terminal caspase activation and recruitment domain (ASC), and inflammatory caspase-1] involved in innate immunity. Here, we provide a unique perspective on the crosstalk between the aggregation-prone proteins involved in AD/PD and the multi-protein inflammasome complex/ASC speck that fuels feed-forward exacerbation of each other, driving neurodegeneration. Failed turnover of protein aggregates (both AD/PD related aggregates and the ASC speck) by protein degradation pathways, prionoid propagation of inflammation by the ASC speck, cross-seeding of protein aggregation by the ASC speck, and pro-aggregatory cleavage of proteins by caspase-1 are some of the mechanisms that exacerbate disease progression. We also review studies that provide this causal framework and highlight how the ASC speck serves as a platform for the propagation and spreading of inflammation and protein aggregation that drives AD and PD.

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TRIM28 SUMOylates and stabilizes NLRP3 to facilitate inflammasome activation

Cited by 72 publications

References 35 publications

Posttranslational Regulation of Inflammasomes, Its Potential as Biomarkers and in the Identification of Novel Drugs Targets

Posttranslational Regulation of Inflammasomes, Its Potential as Biomarkers and in the Identification of Novel Drugs Targets

KAP1/TRIM28: Transcriptional Activator and/or Repressor of Viral and Cellular Programs?

Crosstalk Between the NLRP3 Inflammasome/ASC Speck and Amyloid Protein Aggregates Drives Disease Progression in Alzheimer’s and Parkinson’s Disease

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