Sumoylation Promotes the Stability of the DNA Sensor cGAS and the Adaptor STING to Regulate the Kinetics of Response to DNA Virus

Hu, Mingming; Yang, Qing; Xie, Xueqin; Liao, Chen-Yang; Lin, Heng; Liu, Tiantian; Yin, Lei; Shu, Hong‐Bing

doi:10.1016/j.immuni.2016.08.014

Cited by 266 publications

(240 citation statements)

References 29 publications

Supporting

Mentioning

232

Contrasting

Order By: Relevance

“…Chaperone-mediated autophagy (CMA) may also play a role in STING degradation (Hu et al, 2016). We thus wanted to directly address whether trafficking-mediated STING degradation requires autophagy or CMA.…”

Section: Resultsmentioning

confidence: 99%

Trafficking-Mediated STING Degradation Requires Sorting to Acidified Endolysosomes and Can Be Targeted to Enhance Anti-tumor Response

et al. 2017

View full text Add to dashboard Cite

SUMMARY STING is an ER-associated transmembrane protein that turns on and quickly turns off downstream signaling as it translocates from the ER to vesicles. How STING signaling is attenuated during trafficking remains poorly understood. Here, we show that trafficking-mediated STING degradation requires ER-exit, function of vacuolar ATPase complex, and late stage STING vesicles are sorted to Rab7-positive endolysosomes for degradation. Based on analysis of existing structures, we also identified the helix aa281-297 as a motif required for trafficking-mediated STING degradation. Immuno-EM reveals the size and clustering of STING vesicles and topology of STING on the vesicle. Importantly, blockade of trafficking-mediated STING degradation using bafilomycin A1 specifically enhanced cGAMP-mediated immune response and anti-tumor effect in mice. Together, our findings provide biochemical and imaging evidence for STING degradation by the lysosome, and pinpoint trafficking-mediated STING degradation as a previously unanticipated therapeutic target for enhancing STING signaling in cancer therapy.

show abstract

Section: Resultsmentioning

confidence: 99%

Trafficking-Mediated STING Degradation Requires Sorting to Acidified Endolysosomes and Can Be Targeted to Enhance Anti-tumor Response

et al. 2017

View full text Add to dashboard Cite

show abstract

“…In this study, we show that deamidation of cGAS by UL37 specifically ablated the cGAMP-synthesizing activity of cGAS. Previous studies have shown that cGAS is subjected to diverse post-translational modifications, including sumoylation, glutamylation and phosphorylation (Cui et al, 2017; Hu et al, 2016; Seo et al, 2015; Xia et al, 2016), and direct antagonism by an array of microbial proteins (Aguirre et al, 2017; Wu et al, 2015; Zhang et al, 2016a). How deamidation, of RIG-I and cGAS, cross-talks with these regulatory mechanisms remain unclear and these potential cross-talks, if exist, will connect protein deamidation to other well-established signaling cascades and expand the functional repertoire of protein deamidation in high eukaryotes.…”

Section: Discussionmentioning

confidence: 99%

“…Surprisingly, our understanding in cGAS regulation is in its infancy at best. Previous work has shown that post-translational modifications, including phosphorylation, sumolyation and glutamylation, modulate cGAS enzyme activity directly or indirectly (Cui et al, 2017; Hu et al, 2016; Seo et al, 2015; Xia et al, 2016). Investigating the evasion mechanism of herpes simplex virus 1 (HSV-1) conveyed by the UL37 protein deamidase, we discovered that human and mouse cGAS proteins, but not nonhuman primate cGAS, are targeted for deamidation by UL37.…”

Section: Introductionmentioning

confidence: 99%

Species-Specific Deamidation of cGAS by Herpes Simplex Virus UL37 Protein Facilitates Viral Replication

Zhang

Zhao

et al. 2018

Cell Host & Microbe

144

125

View full text Add to dashboard Cite

SUMMARY Herpes simplex virus-1 (HSV-1) establishes infections in humans and mice but some non-human primates exhibit resistance via unknown mechanisms. Innate immune recognition pathways are highly conserved but are pivotal in determining susceptibility to DNA virus infections. We report that variation of a single amino acid residue in the innate immune sensor cGAS determines species-specific inactivation by HSV-1. The HSV-1 UL37 tegument protein deamidates human and mouse cGAS. Deamidation impairs the ability of cGAS to catalyze cGAMP synthesis, which activates innate immunity. HSV-1 with deamidase-deficient UL37 promotes robust antiviral responses and is attenuated in mice, in a cGAS- and STING-dependent manner. Mutational analyses identified a single asparagine in human and mouse cGAS that is not conserved in many non-human primates. This residue underpins UL37-mediated cGAS deamidation and species permissiveness of HSV-1. Thus, HSV-1 mediates cGAS deamidation for immune evasion and exploits species sequence variation to disarm host defenses.

show abstract

“…MITA/STING -/- mice, kindly provided by Prof. H. B. Shu (Wuhan University, Wuhan) [31], and littermate control wild-type (WT) mice were bred and maintained under specific pathogen-free conditions at the Central Animal Laboratory of Wuhan Institute of Virology, Chinese Academy of Sciences (WIV, CAS. License number: SYXK2014-0034).…”

Section: Methodsmentioning

confidence: 99%

MITA/STING and Its Alternative Splicing Isoform MRP Restrict Hepatitis B Virus Replication

Liu

Zhao

et al. 2017

PLoS ONE

View full text Add to dashboard Cite

An efficient clearance of hepatitis B virus (HBV) requires the coordinated work of both the innate and adaptive immune responses. MITA/STING, an adapter protein of the innate immune signaling pathways, plays a key role in regulating innate and adaptive immune responses to DNA virus infection. Previously, we identified an alternatively spliced isoform of MITA/STING, called MITA-related protein (MRP), and found that MRP could specifically block MITA-mediated interferon (IFN) induction while retaining the ability to activate NF-κB. Here, we asked whether MITA/STING and MRP were able to control the HBV replication. Both MITA/STING and MRP significantly inhibited HBV replication in vitro. MITA overexpression stimulated IRF3-IFN pathway; while MRP overexpression activated NF-κB pathway, suggesting these two isoforms may inhibit HBV replication through different ways. Using a hydrodynamic injection (HI) mouse model, we found that HBV replication was reduced following MITA/STING and MRP expression vectors in mice and was enhanced by the knockout of MITA/STING (MITA/STING-/-). The HBV specific humoral and CD8+ T cell responses were impaired in MITA/STING deficient mice, suggesting the participation of MITA/STING in the initiation of host adaptive immune responses. In summary, our data suggest that MITA/STING and MRP contribute to HBV control via modulation of the innate and adaptive responses.

show abstract

Sumoylation Promotes the Stability of the DNA Sensor cGAS and the Adaptor STING to Regulate the Kinetics of Response to DNA Virus

Cited by 266 publications

References 29 publications

Trafficking-Mediated STING Degradation Requires Sorting to Acidified Endolysosomes and Can Be Targeted to Enhance Anti-tumor Response

Trafficking-Mediated STING Degradation Requires Sorting to Acidified Endolysosomes and Can Be Targeted to Enhance Anti-tumor Response

Species-Specific Deamidation of cGAS by Herpes Simplex Virus UL37 Protein Facilitates Viral Replication

MITA/STING and Its Alternative Splicing Isoform MRP Restrict Hepatitis B Virus Replication

Contact Info

Product

Resources

About