Posttranslational ISGylation of NLRP3 by HERC enzymes facilitates inflammasome activation in models of inflammation.

The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is a crucial component of the innate immune system that initiates inflammatory responses. Posttranslational modifications (PTMs) of NLRP3, including ubiquitination and phosphorylation, control inflammasome activation and determine the intensity of inflammation. However, the role of other PTMs in controlling NLRP3 inflammasome activation remains unclear. This study found that TLR priming induced NLRP3 ISGylation (a type of PTM in which ISG15 covalently binds to the target protein) to stabilize the NLRP3 protein. Viral infection, represented by SARS-COV-2 infection, and type I IFNs induced expression of ISG15 and the predominant E3 ISGylation ligases HECT domain- and RCC1-like domain-containing proteins (HERCs; HERC5 in humans and HERC6 in mice). HERCs promoted NLRP3 ISGylation and inhibited K48-linked ubiquitination and proteasomal degradation, resulting in the enhancement of NLRP3 inflammasome activation. Concordantly, Herc6 deficiency ameliorated NLRP3-dependent inflammation as well as hyperinflammation caused by viral infection. The results illustrate the mechanism by which type I IFNs responses control inflammasome activation and viral infection-induced aberrant NLRP3 activation. This work identifies ISGylation as a PTM of NLRP3, revealing a priming target that modulates NLRP3-dependent immunopathology.

Socioeconomic Factors Contributing to Antibiotic Resistance in China: A Panel Data Analysis.

The relationship between socioeconomic factors and antibiotic resistance (ABR) prevalence remains a knowledge gap in China. In this study, our aim was to examine the association between ABR prevalence and socioeconomic factors across 30 provinces in mainland China. We used two measures of level of ABR: the proportion of methicillin-resistant Staphylococcus aureus (MRSA), third-generation cephalosporin-resistant Escherichia coli (3GCREC), and third-generation cephalosporin-resistant Klebsiella pneumoniae (3GCRKP), and the aggregate resistance. The data of ABR prevalence, education, gross domestic product (GDP) per capita, out-of-pocket (OOP) health expenditure, physician density, hospital bed density, and public toilet density during 2014 and 2018 in 30 provinces in mainland China were included. We examined the association between ABR prevalence and potential contributing socioeconomic factors using panel data modeling. In addition, we explored this relationship in the eastern, central, and western economic zones. Our results indicated that GDP per capita was significantly positively correlated with ABR in mainland China and the eastern economic zone; however, significantly positive associations did not exist in the central and western economic zones. Surprisingly, both higher GDP per capita and higher OOP health expenditure were associated with a higher level of MRSA, but a lower level of 3GCREC; higher physician density was associated with a lower level of MRSA, but a higher level of 3GCREC. In addition, ABR prevalence presented a decline trend during 2014 and 2018. Our study showed the potential associ-ations between resistance and GDP per capita, OOP health expenditure, physician density. It high-lights that the social and economic determinants can be of importance in tacking the development and spread of ABR in mainland China.