-
Categories
-
Pharmaceutical Intermediates
-
Active Pharmaceutical Ingredients
-
Food Additives
- Industrial Coatings
- Agrochemicals
- Dyes and Pigments
- Surfactant
- Flavors and Fragrances
- Chemical Reagents
- Catalyst and Auxiliary
- Natural Products
- Inorganic Chemistry
-
Organic Chemistry
-
Biochemical Engineering
- Analytical Chemistry
-
Cosmetic Ingredient
- Water Treatment Chemical
-
Pharmaceutical Intermediates
Promotion
ECHEMI Mall
Wholesale
Weekly Price
Exhibition
News
-
Trade Service
for host DNA recognition and mediation, both natural and autoimmune against viruses.
Studies have shown that the function and homeostasis of cGAS are dynamically regulated by a variety of post-translational modifications, including ubiquitination, SUMOation, phosphorylation, glutamylation, acetylation, etc.
[1].
In addition, it has recently been reported that cGAS can negatively regulate its mediated antiviral immune response through PARylation and palmitoylation modifications [2, 3].
However, whether there are more other kinds of post-translational modifications in cGAS and how this modification regulates the activity and homeostasis of cGAS, and thus regulates host antiviral immunity and autoimmunity, need to be further studied
.
ISG15 (interferon-stimulating gene 15) is a ubiquitin-like molecule induced by interferon or pathogenic microorganisms that plays an important role
in the host's defense against viral infection.
ISG15 can not only function as a cytokine, but also covalently bind to substrate proteins through a series of enzymatic reactions, a process known as ISG15 modification
.
Non-targeted mass spectrometry studies indicate that there are more than 300 potential substrates for ISG15 modification [4, 5], although the presence of ISG15 modification in cGAS and the physiopathological significance associated with this process have not been reported
.
On October 10, 2022, the Lin Dandan research group of the People's Hospital of Wuhan University published online in the journal Nature Communications The E3 ubiquitin ligase ARIH1 promotes antiviral immunity and autoimmunity by inducing mono-ISGylation and oligomerization of cGAS
。 The team found that E3 ubiquitin ligase ARIH1 enhances the oligomerization level of cGAS after viral infection by catalyzing a single ISG15 modification of lysine at cGAS position 187, thereby promoting antiviral innate immunity as well as autoimmunity
due to Trex1 deletion.
First, the team systematically screened the E3 ubiquitin ligase interacting with cGAS through yeast double hybridization experiments and found that ARIH1 interacted continuously with cGAS
.
Knocking down or knocking out ARIH1 in mouse primary cells significantly inhibits HSV-1 infection or DNA transfection-induced type I interferon expression, and mice with myeloid cell-specific knockout ARIH1 are more susceptible to HSV-1
.
The team then explored the function
of ARIH1 in an autoimmune mouse model resulting from Trex1 knockout.
The results showed that knocking out ARIH1 in myeloid cells of Trex1-/- mice could rescue the lethal autoimmune phenotype caused by Trex1 deficiency, inhibit the differentiation of B cells in the spleen germinal center and the activation of CD8+ T cells, and reduce the infiltration of immune cells in the liver, lungs and heart, as well as the levels
of inflammatory factors and total IgG in peripheral blood.
Further mechanism studies showed that lysine at the 187th position of cGAS was the negative regulatory site of oligomerization, and ARIH1 catalyzed the mono-ISG15 modification of this site of cGAS, lifted the inhibitory effect of this site, promoted cGAS oligomerization and downstream cytokine production, and thus regulated cGAS-mediated antiviral natural immunity and autoimmunity
.
This study elucidates the molecular mechanism of ARIH1, as a novel E3 ligase mediating ISG15 modification, by inducing novel post-translational modifications (mono-ISG15 modification) of cGAS, in the cytoplasmic DNA-induced antiviral immunity and autoimmunity.
It is implied that ARIH1 can be a potential molecular target for certain infectious and autoimmune diseases
.
It is reported that Xiong Tianchen, a postdoctoral fellow jointly trained by Chongqing International Institute of Immunology/Wuhan University Medical Research Institute, Wei Mingcong, a doctoral student of the Institute of Medicine of Wuhan University, and Li Fangxu, a master student, are the co-first authors of this paper, and associate professor Lin Dandan of Wuhan University People's Hospital, Dr.
Zhang Zhidong and Professor Zhong Bo of Zhongnan Hospital of Wuhan University are the co-corresponding authors of this study
。
Original link:
style="line-height: 1.
75em;margin-left: 8px;margin-right: 8px;margin-bottom: 0px;">Pattern maker: Eleven
References
1.
Zhang Z-D & Zhong B (2022) Regulation and function of the cGAS-MITA/STING axis in health and disease.
Cell Insight 1(1).
2.
Wang F, et al.
(2022) Cytoplasmic PARP1 links the genome instability to the inhibition of antiviral immunity through PARylating cGAS.
Mol Cell 82(11):2032-2049 e2037.
3.
Shi C, et al.
(2022) ZDHHC18 negatively regulates cGAS-mediated innate immunity through palmitoylation.
Embo J 41(11):e109272.
4.
Perng YC & Lenschow DJ (2018) ISG15 in antiviral immunity and beyond.
Nat Rev Microbiol 16(7):423-439.
5.
Zhang M, et al.
(2021) ISGylation in Innate Antiviral Immunity and Pathogen Defense Responses: A Review.
Front Cell Dev Biol 9:788410.
Reprint instructions
【Non-original article】The copyright of this article belongs to the author of the article, personal forwarding and sharing is welcome, reprinting is prohibited without the permission of the author, the author has all legal rights, and violators must be investigated
.
