4.7 Article

Ubiquitinated gasdermin D mediates arsenic-induced pyroptosis and hepatic insulin resistance in rat liver

期刊

FOOD AND CHEMICAL TOXICOLOGY
卷 160, 期 -, 页码 -

出版社

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.fct.2021.112771

关键词

Sodium arsenite; Gasdermin D; Pyroptosis; Ubiquitination; Insulin resistance

资金

  1. National Key R&D Program of China [2018YFC1311600]
  2. National Natural Science Foundation of China [NSFC: 81872566]
  3. Liaoning Province People's Livelihood Science and Technology Plan Project [2021JH2/10300048]

向作者/读者索取更多资源

This study demonstrates the involvement of GSDMD in arsenic-induced hepatic insulin resistance (IR) and reveals that NaAsO2 decreases the ubiquitination of GSDMD, reducing its degradation and exacerbating pyroptosis and hepatic IR.
As an environmental toxicant, arsenic exposure may cause insulin resistance (IR). Previous studies have shown that pymptosis plays an important role in the occurrence and development of IR. Although gasdermin D (GSDMD) functions as an executor of pyroptosis, the relationship between GSDMD-mediated pyroptosis and hepatic IR remains unclear. Here, we observed that sodium arsenite (NaAsO 2 ) activated NOD-like receptors containing pyrin domain 3 (NLRP3) inflammasomes, promoted GSDMD activation, induced pymptosis and hepatic IR, while GSDMD knockdown attenuated pyroptosis and hepatic IR caused by NaAsO 2 . However, GSDMD interference did not affect NLRP3 activation. Ubiquitination modification is widely involved in protein regulation and intracellular signal transduction, and whether it regulates GSDMD and affects its degradation, and exerts effects on arsenic-induced pyroptosis remain unclear. We observed that NaAsO 2 reduced the K48- and K63-linked ubiquitination of GSDMD, thereby inhibiting its degradation through the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP), causing GSDMD to accumulate and lyse into GSDMD-N, which promoted pyroptosis. In summary, we demonstrated that GSDMD participated in arsenic-induced hepatic IR. Moreover, NaAsO 2 reduced GSDMD ubiquitination and decreased its intracellular degradation, aggravating pyroptosis and hepatic IR. We have revealed the molecular mechanism underpinning arsenic-induced IR, and we provide potential solutions for the prevention and treatment of type 2 diabetes (T2D).

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