KSHV-encoded ORF45 activates human NLRP1 inflammasome

Yang, Xing; Jing, Zhou; Liu, Chengrong; Qu, Yafei; Wang, Weili; Xiao, Maggie Z X; Zhu, Fanxiu; Liu, Zhenshan; Liang, Qiming

doi:10.1038/s41590-022-01199-x

Cited by 27 publications

(39 citation statements)

References 38 publications

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“…3C proteases from enteroviruses, such as human rhinovirus (HRV), can cleave human NLRP1 between the E130 and G131 residues to relieve its C-terminal fragment for inflammasome assembly [ 53 ]. ORF45 from Kaposi’s sarcoma-associated herpesvirus (KSHV) also facilitates the protease-independent activation of the hNLRP1 inflammasome, which was conserved in primates instead of rodents [ 54 ]. Three paralogues of human NLRP1 are found in mice, including NLRP1a, NLRP1b, and NLRP1c.…”

Section: Organization Of the Canonical Inflammasomesmentioning

confidence: 99%

Activation and Pharmacological Regulation of Inflammasomes

Chen

2022

Biomolecules

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Inflammasomes are intracellular signaling complexes of the innate immune system, which is part of the response to exogenous pathogens or physiological aberration. The multiprotein complexes mainly consist of sensor proteins, adaptors, and pro-caspase-1. The assembly of the inflammasome upon extracellular and intracellular cues drives the activation of caspase-1, which processes pro-inflammatory cytokines IL-1β and IL-18 to maturation and gasdermin-D for pore formation, leading to pyroptosis and cytokine release. Inflammasome signaling functions in numerous infectious or sterile inflammatory diseases, including inherited autoinflammatory diseases, metabolic disorders, cardiovascular diseases, cancers, neurodegenerative disorders, and COVID-19. In this review, we summarized current ideas on the organization and activation of inflammasomes, with details on the molecular mechanisms, regulations, and interventions. The recent developments of pharmacological strategies targeting inflammasomes as disease therapeutics were also covered.

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Section: Organization Of the Canonical Inflammasomesmentioning

confidence: 99%

Activation and Pharmacological Regulation of Inflammasomes

Chen

2022

Biomolecules

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“…Stabilization of an autoinhibited state by the M1184V variant in the full-length NLRP1 multimer would be consistent with the preferential DPP9-binding capabilities this variant exhibits in SPR and co-IP experiments. Interestingly, a recent study also showed formation of DPP9-independent autoinhibited conformations of NLRP1 ( 37 ). Binding of the UPA domain to the linker region between the PYD and NACHT domain mediates this autoinhibition.…”

Section: Discussionmentioning

confidence: 99%

Inflammasome sensor NLRP1 disease variant M1184V promotes autoproteolysis and DPP9 complex formation by stabilizing the FIIND domain

Moecking¹,

Laohamonthonkul²,

Meşe³

et al. 2022

Journal of Biological Chemistry

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“…it's mostly nuclear with some cytoplasmic presence. 18,35 Li and Zhu 35 showed that cytoplasmic localization appears unique to KSHV ORF45 because its homologs of RRV, MHV68, HVS, and EBV are all nuclear. [35][36][37] They also located a typical CRM-dependent nuclear exporting signal (NES) and an adjacent nuclear localization signal (NLS).…”

Section: Transcription and Expressionmentioning

confidence: 99%

“…An NLS-deficient mutant produced lower progeny infectious extracellular viruses while the NES-deficient mutants behaved similarly as the wild type, suggesting a nuclear function(s) of ORF45 is required for progeny virus production. 18,35 The stability of ORF45 protein appears to be regulated by both proteasome-and lysosome-mediated degradation. Cellular ubiquitin E3 ligase SIAH-1 was found to promote the ubiquitination and proteasome degradation of ORF45, 38 while host protein RAB11FIP5 was shown to target ORF45 for lysosomal degradation.…”

Section: Transcription and Expressionmentioning

confidence: 99%

ORF45, a multifunctional immediate early and tegument protein of KSHV

Liang

Zhu

2023

Journal of Medical Virology

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Kaposi sarcoma-associated herpesvirus (KSHV) is the etiological agent of several human diseases, including Kaposi sarcoma, primary effusion lymphoma, and a subset of multicentric Castleman's disease. KSHV uses its gene products to manipulate many aspects of the host responses during its life cycles. Among KSHV-encoded proteins, ORF45 is unique in both temporal and spatial expression: it is expressed as an immediate-early gene product and is an abundant tegument protein contained in the virion. ORF45 is specific to the gammaherpesvirinae subfamily but the homologs share only very limited homology and differ dramatically in protein length. In the past two decades, we and others have shown that ORF45 plays critical roles in immune evasion, viral replication, and virion assembly by targeting various host and viral factors. Herein, we summarize our current knowledge of ORF45 throughout the KSHV life cycle. We discuss the cellular processes targeted by ORF45 with emphasis on the modulation of host innate immune responses and rewiring the host signaling through impacting three major posttranslational modifications: phosphorylation, SUMOylation, and ubiquitination.

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KSHV-encoded ORF45 activates human NLRP1 inflammasome

Cited by 27 publications

References 38 publications

Activation and Pharmacological Regulation of Inflammasomes

Activation and Pharmacological Regulation of Inflammasomes

Inflammasome sensor NLRP1 disease variant M1184V promotes autoproteolysis and DPP9 complex formation by stabilizing the FIIND domain

ORF45, a multifunctional immediate early and tegument protein of KSHV

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