USP18 antagonizes pyroptosis by facilitating selective autophagic degradation of GSDMD

Pyroptosis is a form of cell death that relies on gasdermins-mediated formation pores in the plasma membrane, which subsequently promotes inflammation by releasing immunogenic cellular contents. The inflammation-related feature of pyroptosis underscores its critical role in the host defense and homeostasis. However, uncontrolled pyroptosis is strongly associated with inflammation-related diseases, including ischemic heart disease, rheumatoid arthritis, systemic lupus erythematosus, atherosclerosis, and certain types of cancer. Hence, pyroptosis must be carefully regulated to avoid unintended consequences and maintain balance.

To date, although many studies highlight the importance of PTMs for gasdermins regulation, the detail mechanisms of how these PTMs modulate gasdermins-mediated pyroptosis remain to be fully investigated. GSDMD is the best-characterized member of gasdermins family (including GSDMA-E and pejvakin), and several small-molecule inhibitors of GSDMD have been developed. However, adverse effects and low specificity limit their use. Hence, it is imperative to increase the knowledge of the mechanisms of PTMs-regulated GSDMD activation, which will be a promising approach for drugs development. Although ubiquitination plays a critical role in regulating protein stability, the link between ubiquitination and GSDMD stability remains to be fully elucidated during inflammasomes activation.

The team led by Jun Cui from Sun Yat-sen University has revealed that ubiquitin-specific peptidase 18 (USP18) acts as a key scaffold protein to recruit E3 ubiquitin ligase MIB2 to GSDMD, which mediates ubiquitination on GSDMD at K168 in an enzyme activity-independent manner. The ubiquitination of GSDMD serves as a recognition signal for selective autophagic degradation. Accordingly, overexpression of USP18 decreases the GSDMD protein levels and LPS-triggered inflammation in vivo.

The study was published in Research and the findings demonstrate that USP18 negatively modulates GSDMD-mediated pyroptosis through selective autophagy to avoid excessive and potentially harmful inflammation. Considering the powerful functions of USP18, pharmacological targeting of USP18 counteraction is devised to serve as a potential therapeutic target for inflammation-related diseases.