E3 ligase Nedd4l promotes antiviral innate immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3

Abstract

Ubiquitination is one of the most prevalent protein posttranslational modifications. Here, we show that E3 ligase Nedd4l positively regulates antiviral immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3. Deficiency of Nedd4l significantly impairs type I interferon and proinflammatory cytokine production induced by virus infection both in vitro and in vivo. Nedd4l deficiency inhibits virus-induced ubiquitination of TRAF3, the binding between TRAF3 and TBK1, and subsequent phosphorylation of TBK1 and IRF3. Nedd4l directly interacts with TRAF3 and catalyzes K29-linked ubiquitination of Cys56 and Cys124, two cysteines that constitute zinc fingers, resulting in enhanced association between TRAF3 and E3 ligases, cIAP1/2 and HECTD3, and also increased K48/K63-linked ubiquitination of TRAF3. Mutation of Cys56 and Cys124 diminishes Nedd4l-catalyzed K29-linked ubiquitination, but enhances association between TRAF3 and the E3 ligases, supporting Nedd4l promotes type I interferon production in response to virus by catalyzing ubiquitination of the cysteines in TRAF3.

Samotolisib Attenuates Acute Liver Injury Through Inhibiting Caspase-11-Mediated Pyroptosis Via Regulating E3 Ubiquitin Ligase Nedd4

“…To further explore the mechanism by which ST inhibits caspase-11, we aimed to identify the protein responsible for regulating caspase-11 ubiquitination. In innate immunity, Nedd4l catalyzes the K29-linked ubiquitination of cysteine residues in TNF receptor-associated factor 3, which is key to innate antiviral immunity (Gao et al, 2021). Recent research found that Nedd4 is an important negative regulatory component of the non-canonical inflammasome pathway and that it directly interacts with caspase-11 and mediates the polyubiquitination of K48-linked caspase-11 at multiple K residues and subsequent degradation by the 26S proteasome.…”

“…Nedd4 is well known to play an important role in development and physiological growth (Cao et al, 2008). Moreover, Nedd4 regulates immune cell functions and plays important regulatory roles in adaptive immunity (Liu et al, 2017;Gao et al, 2021). In natural immunity, Nedd4 has an inhibitory effect on non-classical inflammasomes.…”

Insights Into the Biological Role of NEDD4L E3 Ubiquitin Ligase in Human Cancers

“…The original and most familiar function of NEDD4L is to regulate the epithelial Na + channel (ENaC), which is closely related to the fluctuation of blood pressure (23). In addition, NEDD4L also participates in DNA repair, antiviral immunity and tumor development (24)(25)(26). To date, multiple reports have shown that the expression of NEDD4L in cancers is abnormal, and various proteins have been validated to bind with NEDD4L or be ubiquitinated by NEDD4L, thus modulating the cancer development (27).…”

Neurodevelopmental Disorders (NDD) Caused by Genomic Alterations of the Ubiquitin-Proteasome System (UPS): the Possible Contribution of Immune Dysregulation to Disease Pathogenesis

“…It is also understood that the E3 ubiquitin ligases HACE1 ( Mao et al, 2016 ), MID1 ( Chen et al, 2021 ), NEDD4L ( Gao et al, 2021 ), PRKN ( Sliter et al, 2018 ), RNF125 ( Arimoto et al, 2007 ), RNF170 ( Song et al, 2020 ), RNF216 ( Nakhaei et al, 2009 ), STUB1 ( Zhou et al, 2018 ), as well as UBE3A ( Furumai et al, 2019 ) are involved in antiviral innate defense and the generation of type I interferon (IFN) responses ( Figure 2 ). Again, besides NEDD4L, all these genes encode ligases involved in type I IFN negative feedback loops and, as such any dysfunction, would lead to uncontrolled type I IFN responses.…”