PXD040291

PXD040291 is an original dataset announced via ProteomeXchange.

Title	A novel HERC4-dependent glue degrader targeting STING
Description	Stimulator of interferon genes (STING) is a central component of the pathway sensing the presence of cytosolic nucleic acids, having a key role in type I interferon innate immune response. Localized at the endoplasmic reticulum (ER), STING becomes activated by cGAMP, which is generated by the intracellular DNA sensor cyclic GMP-AMP synthase (cGAS). Due to its critical role in physiological function and its’ involvement in a variety of diseases, STING has been a notable focus for drug discovery. Recent advances in drug discovery allow the targeting of proteins previously considered “un-druggable” by novel mechanism of actions. Molecular glue degraders are defined as the compounds leading targeted protein degradation (TPD) by creating novel ligase-substrate interactions. Here, we identified AK59 as a novel molecular glue degrader for STING. A genome-wide, CRISPR/Cas9 knockout screen showed that the compound-mediated degradation of STING by AK59 is compromised by the loss of HECT and RLD domain containing E3 ubiquitin protein ligase 4 (HERC4), ubiquitin-like modifier activating enzyme 5 (UBA5) and ubiquitin like modifier activating enzyme 6 (UBA6). While UBA5 and UBA6 could be the auxiliary factors for AK59 activity, our results indicate that HERC4 is the main E3 ligase for the observed degradation mechanism. Validation by individual CRISPR knockouts, co-immunoprecipitations, as well as proximity mediated reporter assays suggested that AK59 functions as a glue degrader by forming a novel interaction between STING and HERC4. Furthermore, our data reveals that AK59 was effective on the most common pathological STING mutations that cause STING-associated vasculopathy with onset in infancy (SAVI), suggesting a potential clinical application of this mechanism. Thus, these findings not only reveal a novel mechanism for compound-induced degradation of STING but also utilize HERC4 as potential E3 ligase that for TPD, enabling novel therapeutic applications.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:49:36.496.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD040291
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Andreas Hofmann
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-02-20 08:28:34	ID requested
1	2023-06-22 06:47:09	announced
⏵ 2	2024-10-22 05:49:36	announced	2024-10-22: Updated project metadata.

10.6019/PXD040291;

submitter keyword: targeted protein degradation, HERC4, glue degrader, TPD,STING

Andreas Hofmann
contact affiliation	Novartis Institutes for BioMedical Research, Basel, Switzerland
contact email	andreas.hofmann@novartis.com
lab head
Andreas Hofmann
contact affiliation	NIBR
contact email	andreas.hofmann@novartis.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD040291
     1. Label: PRIDE project
     2. Name: A novel HERC4-dependent glue degrader targeting STING