HPV E7 inhibits cell pyroptosis by promoting TRIM21-mediated degradation and ubiquitination of the IFI16 inflammasome

Abstract

Human papillomavirus (HPV) is a DNA virus that causes sexually transmitted infections. The HPV oncoprotein E7 plays a critical role in the regulation of host immunity to promote the immune escape of HPV and the occurrence of cervical cancer or genital warts. Pyroptosis, a highly inflammatory form of programmed cell death, can be induced by inflammasomes and acts as a defense against pathogenic infection. However, whether HPV E7 can regulate cell pyroptosis to evade immune surveillance has not been determined. In this study, we found that HPV E7 could inhibit cell pyroptosis induced by transfection with dsDNA. The activation of the inflammasome, and the production of IL-18 and IL-1β were also restrained by HPV E7. Mass spectrometry and immunoprecipitation showed that HPV E7 interacted with IFI16 and TRIM21. We also discovered that HPV E7 recruited the E3 ligase TRIM21 to ubiquitinate and degrade the IFI16 inflammasome, leading to the inhibition of cell pyroptosis and self-escape from immune surveillance. Thus, our study reveals an important immune escape mechanism in HPV infection and may provide targets for the development of a novel immunotherapeutic strategy to effectively restore antiviral immunity.

Pyroptosis: mechanisms and diseases

“…HPV E7 recruited E3 ligase TRIM21 to cause ubiquitination and degradation of IFI16 inflammasome, resulting in suppression of pyroptosis and self-escape of immune monitoring, revealing a significant immune escape mechanism in HPV infection, which may provide a novel target for the development of immunotherapy strategy for effective restoration of antiviral immunity. 399 …”

Human papillomavirus E6 and E7: What remains?

“…5 ), and E7 has been reported to inhibit the interferon response through downregulation of the cGAS/STING response [ 123 ], although this is not yet clear and different HPV types may employ different means to do this [ [124] , [125] , [126] ]. E7 also recruits the TRIM21 ubiquitin ligase to degrade the IFI16 inflammasome, thereby contributing to the evasion of immune surveillance [ 127 ]. The contribution of insulin-activated transcription has recently come to the fore; stimulation of the insulin receptor leads to transactivation of a number of genes via recruitment of p300 (a target of E7 - [ 47 ]) and TIP60 (an E6 target - [ 45 ]) leading to chromatin modification and upregulated transcription of genes involved in glucose metabolism [ 128 ].…”

“…E7 also recruits the TRIM21 ubiquitin ligase to degrade IFI16, a viral DNA sensor, thus inhibiting inflammasome-induced pyroptosis [ 127 ]. Another DNA-detection protein, Toll-like receptor 9 (TLR9), is also suppressed in keratinocytes expressing E6/E7 [ 203 ], although in this case the downregulation seems to be at the transcriptional level [ 204 , 205 ].…”

TRIM21/Ro52 - Roles in Innate Immunity and Autoimmune Disease

“…Human papillomavirus presents an alternative method for immune escape by utilising the oncoprotein E7. This recruits TRIM21 to promote the K33-linked ubiquitination and degradation of the host IFI16 inflammasome ( 94 ).…”