bims-inflin 2024-04-14 papers

on Inflammasome and infection

Issue of 2024‒04‒14
two papers selected by
Juliane Cristina Ribeiro Fernandes, Faculdade de Medicina de Ribeirão Preto

ROS-dependent S-palmitoylation activates cleaved and intact gasdermin D.
Advances in the mechanism of inflammasomes activation in herpes virus infection.

Nature. 2024 Apr 10.

ROS-dependent S-palmitoylation activates cleaved and intact gasdermin D.

Gang Du, Liam B Healy, Liron David, Caitlin Walker, Tarick J El-Baba, Corinne A Lutomski, Byoungsook Goh, Bowen Gu, Xiong Pi, Pascal Devant, Pietro Fontana, Ying Dong, Xiyu Ma, Rui Miao, Arumugam Balasubramanian, Robbins Puthenveetil, Anirban Banerjee, Hongbo R Luo, Jonathan C Kagan, Sungwhan F Oh, Carol V Robinson, Judy Lieberman, Hao Wu.

Gasdermin D (GSDMD) is the common effector for cytokine secretion and pyroptosis downstream of inflammasome activation and was previously shown to form large transmembrane pores upon cleavage by inflammatory caspases to generate the GSDMD N-terminal domain (GSDMD-NT)1-10. Here we report that GSDMD Cys191 is S-palmitoylated and palmitoylation is required for pore formation. S-palmitoylation, which does not affect GSDMD cleavage, is augmented by mitochondria-generated reactive oxygen species (ROS). Surprisingly, cleavage-deficient D275A GSDMD is also palmitoylated after inflammasome stimulation or treatment with ROS activators, and causes pyroptosis, although less efficiently than palmitoylated GSDMD-NT. Palmitoylated, but not unpalmitoylated, full-length GSDMD induces liposome leakage, and forms a pore similar in structure to GSDMD-NT pores shown by cryogenic electron microscopy. zDHHC5 and zDHHC9 are the major palmitoyltransferases that mediate GSDMD palmitoylation, and their expression is upregulated by inflammasome activation and ROS. The other human gasdermins are also palmitoylated in their N-termini. These data challenge the concept that cleavage is the only trigger for GSDMD activation. They suggest that reversible palmitoylation is a checkpoint for pore formation by both GSDMD-NT and intact GSDMD that serves as a general switch for the activation of this pore-forming family.

DOI: https://doi.org/10.1038/s41586-024-07373-5
Front Immunol. 2024 ;15 1346878

Advances in the mechanism of inflammasomes activation in herpes virus infection.

Hourui Chen, Zhijie Jian, Tong Xu, Lei Xu, Lishuang Deng, Lina Shao, Leyi Zhang, Li He, Youyou Li, Ling Zhu.

  Herpesviruses, prevalent DNA viruses with a double-stranded structure, establish enduring infections and play a part in various diseases. Despite their deployment of multiple tactics to evade the immune system, both localized and systemic inflammatory responses are triggered by the innate immune system's recognition of them. Recent progress has offered more profound understandings of the mechanisms behind the activation of the innate immune system by herpesviruses, specifically through inflammatory signaling. This process encompasses the initiation of an intracellular nucleoprotein complex, the inflammasome associated with inflammation.Following activation, proinflammatory cytokines such as IL-1β and IL-18 are released by the inflammasome, concurrently instigating a programmed pathway for cell death. Despite the structural resemblances between herpesviruses, the distinctive methods of inflammatory activation and the ensuing outcomes in diseases linked to the virus exhibit variations.The objective of this review is to emphasize both the similarities and differences in the mechanisms of inflammatory activation among herpesviruses, elucidating their significance in diseases resulting from these viral infections.Additionally, it identifies areas requiring further research to comprehensively grasp the impact of this crucial innate immune signaling pathway on the pathogenesis of these prevalent viruses.

Keywords:  herpesviruses; inflammasomes; inflammatory factors; innate immunity; signaling pathways

DOI:  https://doi.org/10.3389/fimmu.2024.1346878