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Cysteine Allostery Governs STING Oli...

Chan, Rebecca Jing Mun,

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Cysteine Allostery Governs STING Oligomerization and Function /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Cysteine Allostery Governs STING Oligomerization and Function // Rebecca Jing Mun Chan.
Author:	Chan, Rebecca Jing Mun,
Description:	1 electronic resource (162 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
Contained By:	Dissertations Abstracts International86-12B.
Subject:	Infections. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31974608
ISBN:	9798311949477

Cysteine Allostery Governs STING Oligomerization and Function /
Chan, Rebecca Jing Mun,

Cysteine Allostery Governs STING Oligomerization and Function /Rebecca Jing Mun Chan. - 1 electronic resource (162 pages)

Source: Dissertations Abstracts International, Volume: 86-12, Section: B.

The cGAS-STING pathway is an essential part of our innate immune system that senses mislocalized DNA and initiates an immune response. This is beneficial during pathogen invasion or to promote tumor surveillance, but overactivation of the pathway is associated with many autoimmune and inflammatory diseases. Because of its significance in these disease contexts, it is important to be able to develop modulators of STING signaling, especially in the inhibitor landscape for inflammatory conditions, which has been relatively barren compared to STING agonists. In order to do so, we must first understand the precise mechanisms by which STING is activated and regulated on a cellular level. Using biochemical and cell biology techniques, I found that STING oligomerizes rapidly on the ER upon cGAMP stimulation, and although disulfide formation is not necessary for this process, it is still required for activity. I also found that STING is palmitoylated both basally and in a cGAMP-induced manner. Although inhibiting palmitoylation at cysteine 91 has been the most common therapeutic strategy to inhibit STING signaling, I found that C91-targeting compounds may also affect STING oligomerization through allosteric modulation of disulfide-forming C148, although they exhibit highly context-dependent efficacies.Additionally, I found that STING is basally palmitoylated at C64 and that this is required for STING function. In the absence of palmitoylation at this site, STING forms excessive basal disulfide-linked dimers and larger non-functional oligomers. These oligomers are still able to interact with the downstream effector proteins TBK1 and IRF3, but do not allow them to interact with each other productively. Importantly, C64 is the most evolutionarily conserved cysteine in STING's transmembrane domain and is also important for STING's autophagy function.Together, I have discovered a novel palmitoylation site on STING's transmembrane domain that is critical for forming the correct oligomer assembly, as well as a unique crosstalk between the transmembrane and cytosolic domains of STING. Although the aforementioned cysteines may seem like attractive targets for STING inhibition, they all contain their own limitations and caveats. However, because their mutation or engagement converges on dysfunctional oligomerization, we propose that oligomerization is the most promising way to inhibit signaling and take inspiration from STING's own C-terminal tail autoinhibition mechanism as a strategy to do so. These findings provide a more detailed molecular picture of the precise requirements of STING activation, the limitations of current STING inhibitors, and a roadmap going forward on better ways of mitigating STING signaling in autoimmunity and inflammation.

English

ISBN: 9798311949477Subjects--Topical Terms:

1621997
Infections.

Cysteine Allostery Governs STING Oligomerization and Function /
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520 $a The cGAS-STING pathway is an essential part of our innate immune system that senses mislocalized DNA and initiates an immune response. This is beneficial during pathogen invasion or to promote tumor surveillance, but overactivation of the pathway is associated with many autoimmune and inflammatory diseases. Because of its significance in these disease contexts, it is important to be able to develop modulators of STING signaling, especially in the inhibitor landscape for inflammatory conditions, which has been relatively barren compared to STING agonists. In order to do so, we must first understand the precise mechanisms by which STING is activated and regulated on a cellular level. Using biochemical and cell biology techniques, I found that STING oligomerizes rapidly on the ER upon cGAMP stimulation, and although disulfide formation is not necessary for this process, it is still required for activity. I also found that STING is palmitoylated both basally and in a cGAMP-induced manner. Although inhibiting palmitoylation at cysteine 91 has been the most common therapeutic strategy to inhibit STING signaling, I found that C91-targeting compounds may also affect STING oligomerization through allosteric modulation of disulfide-forming C148, although they exhibit highly context-dependent efficacies.Additionally, I found that STING is basally palmitoylated at C64 and that this is required for STING function. In the absence of palmitoylation at this site, STING forms excessive basal disulfide-linked dimers and larger non-functional oligomers. These oligomers are still able to interact with the downstream effector proteins TBK1 and IRF3, but do not allow them to interact with each other productively. Importantly, C64 is the most evolutionarily conserved cysteine in STING's transmembrane domain and is also important for STING's autophagy function.Together, I have discovered a novel palmitoylation site on STING's transmembrane domain that is critical for forming the correct oligomer assembly, as well as a unique crosstalk between the transmembrane and cytosolic domains of STING. Although the aforementioned cysteines may seem like attractive targets for STING inhibition, they all contain their own limitations and caveats. However, because their mutation or engagement converges on dysfunctional oligomerization, we propose that oligomerization is the most promising way to inhibit signaling and take inspiration from STING's own C-terminal tail autoinhibition mechanism as a strategy to do so. These findings provide a more detailed molecular picture of the precise requirements of STING activation, the limitations of current STING inhibitors, and a roadmap going forward on better ways of mitigating STING signaling in autoimmunity and inflammation.
546 $a English
590 $a School code: 0212
650 4 $a Infections. $3 1621997
650 4 $a Immunosuppressive agents. $3 1531038
650 4 $a Pathogens. $3 3540520
650 4 $a Antigen presentation. $3 3564522
650 4 $a Immunotherapy. $3 597370
650 4 $a Disease. $3 705846
650 4 $a Cancer therapies. $3 3557730
650 4 $a Mutation. $3 837917
650 4 $a Immune system. $3 689864
650 4 $a Bacteria. $3 550366
650 4 $a Lymphocytes. $3 895384
650 4 $a Autophagy. $3 2045493
650 4 $a Agonists. $3 3823605
650 4 $a Inflammation. $3 662994
650 4 $a Phosphorylation. $3 816803
650 4 $a Viral infections. $3 3540521
650 4 $a Senescence. $3 3561729
650 4 $a Mitochondrial DNA. $3 558956
650 4 $a Interferon. $3 671927
650 4 $a Drug dosages. $3 3557732
650 4 $a Immunology. $3 611031
690 $a 0982
710 2 $a Stanford University. $e degree granting institution. $3 3765820
720 1 $a Li, Lingyin $e degree supervisor.
773 0 $t Dissertations Abstracts International $g 86-12B.
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791 $a Ph.D.
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