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Cysteine Allostery Governs STING Oli...

Chan, Rebecca Jing Mun,

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Cysteine Allostery Governs STING Oligomerization and Function /

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Cysteine Allostery Governs STING Oligomerization and Function // Rebecca Jing Mun Chan.
作者:	Chan, Rebecca Jing Mun,
面頁冊數:	1 electronic resource (162 pages)
附註:	Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
Contained By:	Dissertations Abstracts International86-12B.
標題:	Infections. -
電子資源:	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.
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