Molecule Information

General Information of the Molecule (ID: Mol04419)

• Name: Stimulator of interferon genes protein (STING1) ,Homo sapiens
• Synonyms: Endoplasmic reticulum interferon stimulator ; Mediator of IRF3 activation ; Transmembrane protein 173
• Molecule Type: Protein
• Gene Name: STING1
• Gene ID: 340061
• Sequence:
  MPHSSLHPSIPCPRGHGAQKAALVLLSACLVTLWGLGEPPEHTLRYLVLHLASLQLGLLL
  NGVCSLAEELRHIHSRYRGSYWRTVRACLGCPLRRGALLLLSIYFYYSLPNAVGPPFTW
  M LALLGLSQALNILLGLKGLAPAEISAVCEKGNFNVAHGLAWSYYIGYLRLILPELQAR
  IR TYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLPQQTGDHAGIKD
  RVY SNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKLFCRTLE
  DILA DAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEVTVGSLKTSAVPSTS
  TMSQE PELLISGMEKPLPLRTDFS
• Function: Facilitator of innate immune signaling that acts as a sensorof cytosolic DNA from bacteria and viruses and promotes the productionof type I interferon . Innate immuneresponse is triggered in response to non-CpG double-stranded DNA fromviruses and bacteria delivered to the cytoplasm . Actsby binding cyclic dinucleotides: recognizes and binds cyclic di-GMP , a second messenger produced by bacteria, cyclic UMP-AMP, and cyclic GMP-AMP , a messenger produced by CGASin response to DNA virus in the cytosol . Upon binding to c-di-GMP, cUAMP or cGAMP, STING1oligomerizes, translocates from the endoplasmic reticulum and isphosphorylated by TBK1 on the pLxIS motif, leading to recruitment andsubsequent activation of the transcription factor IRF3 to induceexpression of type I interferon and exert a potent anti-viral state. Exhibits 2',3' phosphodiesterlinkage-specific ligand recognition: can bind both 2'-3' linked cGAMP and 3'-3' linked cGAMP but is preferentially activated by2'-3' linked cGAMP .The preference for 2'-3'-cGAMP, compared to other linkage isomers isprobably due to the ligand itself, whichs adopts an organized free-ligand conformation that resembles the STING1-bound conformation andpays low energy costs in changing into the active conformation. In addition to promote the production of type Iinterferons, plays a direct role in autophagy . Following cGAMP-binding, STING1 buds from theendoplasmic reticulum into COPII vesicles, which then form theendoplasmic reticulum-Golgi intermediate compartment . The ERGIC serves as the membrane source for WIPI2recruitment and LC3 lipidation, leading to formation of autophagosomesthat target cytosolic DNA or DNA viruses for degradation by thelysosome . Promotes autophagy by acting as a protonchannel that directs proton efflux from the Golgi to facilitateMAP1LC3B/LC3B lipidation . The autophagy- andinterferon-inducing activities can be uncoupled and autophagy inductionis independent of TBK1 phosphorylation . Autophagy is also triggered upon infection bybacteria: following c-di-GMP-binding, which is produced by live Gram-positive bacteria, promotes reticulophagy . May beinvolved in translocon function, the translocon possibly being able toinfluence the induction of type I interferons . May beinvolved in transduction of apoptotic signals via its association withthe major histocompatibility complex class II .{ECO:0000250|UniProtKB:Q3TBT3, ECO:0000269|PubMed:18724357,ECO:0000269|PubMed:18818105, ECO:0000269|PubMed:19433799,ECO:0000269|PubMed:19776740, ECO:0000269|PubMed:21947006,ECO:0000269|PubMed:22394562, ECO:0000269|PubMed:23027953,ECO:0000269|PubMed:23258412, ECO:0000269|PubMed:23707065,ECO:0000269|PubMed:23722158, ECO:0000269|PubMed:23747010,ECO:0000269|PubMed:23910378, ECO:0000269|PubMed:25636800,ECO:0000269|PubMed:25704810, ECO:0000269|PubMed:26150511,ECO:0000269|PubMed:26229117, ECO:0000269|PubMed:26300263,ECO:0000269|PubMed:27801882, ECO:0000269|PubMed:29973723,ECO:0000269|PubMed:30568238, ECO:0000269|PubMed:30842653,ECO:0000269|PubMed:30842659, ECO:0000269|PubMed:30842662,ECO:0000269|PubMed:35045565, ECO:0000269|PubMed:35388221,ECO:0000269|PubMed:36808561, ECO:0000269|PubMed:37379839,ECO:0000269|PubMed:37535724, ECO:0000269|PubMed:37832545,ECO:0000269|PubMed:39255680}.; Antiviral activity is antagonized byoncoproteins, such as papillomavirus protein E7 and adenovirusearly E1A protein . Such oncoproteins prevent theability to sense cytosolic DNA .{ECO:0000269|PubMed:26405230}.
• Uniprot ID: STING_HUMAN
• Ensembl ID: ENSG0000018458414
• HGNC ID: HGNC:27962

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  RTDM: Regulation by the Disease Microenvironment

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Bortezomib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Multiple myeloma [ICD-11: 2A83.0] [1]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Resistant Drug: Bortezomib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NCI-H929 cells; Bone marrow; Homo sapiens (Human); CVCL_1600
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-kappaB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-kappaB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma.

References

• Ref 1: Simultaneously Targeting Two Coupled Signalling Molecules in the Mesenchymal Stem Cell Support Efficiently Sensitises the Multiple Myeloma Cell Line H929 to Bortezomib. Int J Mol Sci. 2023 May 2;24(9):8157.