HERC6, a member of the HECT domain-and RCC1-like domain-containing proteins family, is an IFN-induced E3 ubiquitin ligase. It is involved in the ISGylation process, which conjugates the ubiquitin-like modifier IFN-stimulated gene 15 (ISG15) to substrates. This process is crucial for innate immune responses, regulating pathways such as STING-TBK1 signaling, NLRP3 inflammasome activation, and cGAS-mediated innate immunity [2,3,4].

HERC6 deficiency in human keratinocytes leads to enhanced induction of interferon-stimulated genes (ISGs) upon treatment with a double-stranded (ds) DNA STING activator cGAMP, due to sustained STING-TBK1 signaling through modulation of LATS2 and TBK1 activity. This uncovers more robust ISG responses in female keratinocytes, indicating HERC6 as a negative regulator of ISG expression specific to dsDNA sensing and a regulator of female-biased immune responses [1]. In mice, Herc6 deficiency suppresses herpes simplex virus 1 infection-induced type I IFN responses and facilitates viral replication both in vitro and in vivo, as HERCs (HERC6 in mice) facilitate STING activation by mediating ISGylation of STING at K150, preventing its K48-linked ubiquitination and degradation [2]. Also, Herc6 deficiency ameliorates NLRP3-dependent inflammation as well as hyperinflammation caused by viral infection, as HERCs promote NLRP3 ISGylation and inhibit its K48-linked ubiquitination and proteasomal degradation [3]. Mice deficient in Herc6 are more vulnerable to herpes simplex virus 1 infection, as deficiency of ISGylation attenuates the downstream inflammatory gene expression induced by the cGAS-STING axis and the antiviral ability [4].

In conclusion, HERC6 plays a vital role in innate immune responses through its function in ISGylation. Gene knockout studies in mice have revealed its significance in regulating antiviral responses, inflammation, and immune-related gene expression. These findings suggest that HERC6 could be a potential target for treating diseases related to immune dysregulation, such as viral infections and certain autoimmune diseases [1,2,3,4].

References:

1. Uppala, Ranjitha, Sarkar, Mrinal K, Young, Kelly Z, Kahlenberg, J Michelle, Gudjonsson, Johann E. 2024. HERC6 regulates STING activity in a sex-biased manner through modulation of LATS2/VGLL3 Hippo signaling. In iScience, 27, 108986. doi:10.1016/j.isci.2024.108986. https://pubmed.ncbi.nlm.nih.gov/38327798/

2. Qin, Ying, Wang, Min, Meng, Xintong, Zhao, Wei, Zheng, Xuexing. 2024. ISGylation by HERCs facilitates STING activation. In Cell reports, 43, 114135. doi:10.1016/j.celrep.2024.114135. https://pubmed.ncbi.nlm.nih.gov/38652662/

3. Qin, Ying, Meng, Xintong, Wang, Mengge, Zhao, Chunyuan, Zhao, Wei. 2023. Posttranslational ISGylation of NLRP3 by HERC enzymes facilitates inflammasome activation in models of inflammation. In The Journal of clinical investigation, 133, . doi:10.1172/JCI161935. https://pubmed.ncbi.nlm.nih.gov/37651190/

4. Chu, Lei, Qian, Li, Chen, Yu, Wang, Chen, Cui, Shufang. 2024. HERC5-catalyzed ISGylation potentiates cGAS-mediated innate immunity. In Cell reports, 43, 113870. doi:10.1016/j.celrep.2024.113870. https://pubmed.ncbi.nlm.nih.gov/38421872/