STING_EIDHE
ID STING_EIDHE Reviewed; 379 AA.
AC A0A291NUI5;
DT 25-MAY-2022, integrated into UniProtKB/Swiss-Prot.
DT 20-DEC-2017, sequence version 1.
DT 03-AUG-2022, entry version 11.
DE RecName: Full=Stimulator of interferon genes protein {ECO:0000250|UniProtKB:Q86WV6};
DE Short=STING {ECO:0000303|PubMed:29478775};
GN Name=STING1 {ECO:0000250|UniProtKB:Q86WV6};
GN Synonyms=STING {ECO:0000303|PubMed:29478775};
OS Eidolon helvum (Straw-colored fruit bat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Chiroptera; Megachiroptera; Pteropodidae;
OC Pteropodinae; Eidolon.
OX NCBI_TaxID=77214;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND MUTAGENESIS OF HIS-358.
RX PubMed=29478775; DOI=10.1016/j.chom.2018.01.006;
RA Xie J., Li Y., Shen X., Goh G., Zhu Y., Cui J., Wang L.F., Shi Z.L.,
RA Zhou P.;
RT "Dampened STING-dependent interferon activation in bats.";
RL Cell Host Microbe 23:297-301(2018).
CC -!- FUNCTION: Facilitator of innate immune signaling that acts as a sensor
CC of cytosolic DNA from bacteria and viruses and promotes low production
CC of type I interferon (IFN-alpha and IFN-beta) (PubMed:29478775).
CC Compared to other mammals, STING1-dependent type I interferon induction
CC is strongly reduced in bats, suggesting that the cGAS-STING pathway
CC promotes a limited inflammatory response (PubMed:29478775). Innate
CC immune response is triggered in response to non-CpG double-stranded DNA
CC from viruses and bacteria delivered to the cytoplasm (By similarity).
CC Acts by binding cyclic dinucleotides: recognizes and binds cyclic di-
CC GMP (c-di-GMP), a second messenger produced by bacteria, and cyclic
CC GMP-AMP (cGAMP), a messenger produced by CGAS in response to DNA virus
CC in the cytosol (By similarity). Upon binding of c-di-GMP or cGAMP,
CC STING1 oligomerizes, translocates from the endoplasmic reticulum and is
CC phosphorylated by TBK1 on the pLxIS motif, leading to recruitment and
CC subsequent activation of the transcription factor IRF3 to induce
CC expression of type I interferon and exert a potent anti-viral state (By
CC similarity). In addition to promote the production of type I
CC interferons, plays a direct role in autophagy (By similarity).
CC Following cGAMP-binding, STING1 buds from the endoplasmic reticulum
CC into COPII vesicles, which then form the endoplasmic reticulum-Golgi
CC intermediate compartment (ERGIC) (By similarity). The ERGIC serves as
CC the membrane source for WIPI2 recruitment and LC3 lipidation, leading
CC to formation of autophagosomes that target cytosolic DNA or DNA viruses
CC for degradation by the lysosome (By similarity). The autophagy- and
CC interferon-inducing activities can be uncoupled and autophagy induction
CC is independent of TBK1 phosphorylation (By similarity).
CC {ECO:0000250|UniProtKB:Q86WV6, ECO:0000269|PubMed:29478775}.
CC -!- SUBUNIT: Homodimer; forms a homodimer in absence of cyclic nucleotide
CC (c-di-GMP or cGAMP) (By similarity). Homotetramer; in presence of
CC cyclic nucleotide (c-di-GMP or cGAMP), forms tetramers and higher-order
CC oligomers through side-by-side packing (By similarity). Interacts (when
CC phosphorylated) with IRF3; following activation and phosphorylation on
CC the pLxIS motif by TBK1, recruits IRF3 (By similarity). Interacts with
CC TBK1; when homodimer, leading to subsequent production of IFN-beta (By
CC similarity). {ECO:0000250|UniProtKB:Q86WV6}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:Q3TBT3}; Multi-pass membrane protein
CC {ECO:0000255}. Cytoplasm, perinuclear region
CC {ECO:0000250|UniProtKB:Q86WV6}. Endoplasmic reticulum-Golgi
CC intermediate compartment membrane {ECO:0000250|UniProtKB:Q3TBT3};
CC Multi-pass membrane protein {ECO:0000255}. Golgi apparatus membrane
CC {ECO:0000250|UniProtKB:Q86WV6}; Multi-pass membrane protein
CC {ECO:0000255}. Cytoplasmic vesicle, autophagosome membrane
CC {ECO:0000250|UniProtKB:Q3TBT3}; Multi-pass membrane protein
CC {ECO:0000255}. Mitochondrion outer membrane
CC {ECO:0000250|UniProtKB:Q3TBT3}; Multi-pass membrane protein
CC {ECO:0000255}. Cell membrane {ECO:0000250|UniProtKB:Q3TBT3}; Multi-pass
CC membrane protein {ECO:0000255}. Note=In response to double-stranded DNA
CC stimulation, translocates from the endoplasmic reticulum through the
CC endoplasmic reticulum-Golgi intermediate compartment and Golgi to post-
CC Golgi vesicles, where the kinase TBK1 is recruited (By similarity).
CC Upon cGAMP-binding, translocates to the endoplasmic reticulum-Golgi
CC intermediate compartment (ERGIC) in a process that is dependent on
CC COPII vesicles; STING1-containing ERGIC serves as a membrane source for
CC LC3 lipidation, which is a key step in autophagosome biogenesis (By
CC similarity). {ECO:0000250|UniProtKB:Q86WV6}.
CC -!- DOMAIN: In absence of cGAMP, the transmembrane and cytoplasmic regions
CC interact to form an integrated, domain-swapped dimeric assembly (By
CC similarity). In absence of cyclic nucleotide (c-di-GMP or cGAMP), the
CC protein is autoinhibited by an intramolecular interaction between the
CC cyclic dinucleotide-binding domain (CBD) and the C-terminal tail (CTT)
CC (By similarity). Following cGAMP-binding, the cyclic dinucleotide-
CC binding domain (CBD) is closed, leading to a 180 degrees rotation of
CC the CBD domain relative to the transmembrane domain. This rotation is
CC coupled to a conformational change in a loop on the side of the CBD
CC dimer, which leads to the formation of the STING1 tetramer and higher-
CC order oligomers through side-by-side packing (By similarity).
CC {ECO:0000250|UniProtKB:E1C7U0, ECO:0000250|UniProtKB:Q86WV6}.
CC -!- DOMAIN: The pLxIS motif constitutes an IRF3-binding motif: following
CC phosphorylation by TBK1, the phosphorylated pLxIS motif of STING1
CC recruits IRF3 (By similarity). IRF3 is then phosphorylated and
CC activated by TBK1 to induce type-I interferons and other cytokines (By
CC similarity). {ECO:0000250|UniProtKB:Q86WV6}.
CC -!- DOMAIN: The N-terminal domain interacts with glycerophospholipids and
CC phospholipids. {ECO:0000250|UniProtKB:Q86WV6}.
CC -!- PTM: Phosphorylation by TBK1 leads to activation and production of IFN-
CC beta (By similarity). Following cyclic nucleotide (c-di-GMP or cGAMP)-
CC binding, activation and translocation from the endoplasmic reticulum,
CC STING1 is phosphorylated by TBK1 at Ser-366 in the pLxIS motif (By
CC similarity). The phosphorylated pLxIS motif constitutes an IRF3-binding
CC motif, leading to recruitment of the transcription factor IRF3 to
CC induce type-I interferons and other cytokines (By similarity). In
CC contrast, lacks phosphorylation site at position 358, leading to
CC reduced production of type-I interferons and other cytokines
CC (PubMed:29478775). {ECO:0000250|UniProtKB:Q86WV6,
CC ECO:0000269|PubMed:29478775}.
CC -!- SIMILARITY: Belongs to the STING family. {ECO:0000305}.
CC -!- CAUTION: The cGAS-STING pathway promotes a limited inflammatory
CC response in bats (PubMed:29478775). This may be caused by the absence
CC of the phosphorylation site at position 358, which is required to
CC production of type-I interferons and other cytokines in other species
CC (PubMed:29478775). The dampened cGAS-STING pathway may explain why bats
CC show an increased tolerance to highly pathogenic viruses, such as
CC coronaviruses, and serve as a virus reservoir (PubMed:29478775).
CC {ECO:0000269|PubMed:29478775}.
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DR EMBL; MF174844; ATJ03487.1; -; mRNA.
DR GO; GO:0000421; C:autophagosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0031410; C:cytoplasmic vesicle; IEA:UniProtKB-KW.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0033116; C:endoplasmic reticulum-Golgi intermediate compartment membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005741; C:mitochondrial outer membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0035438; F:cyclic-di-GMP binding; IEA:InterPro.
DR GO; GO:0002218; P:activation of innate immune response; IEA:InterPro.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0032481; P:positive regulation of type I interferon production; IEA:InterPro.
DR CDD; cd12146; STING_C; 1.
DR Gene3D; 3.40.50.12100; -; 1.
DR InterPro; IPR029158; STING.
DR InterPro; IPR033952; STING_C.
DR InterPro; IPR038623; STING_C_sf.
DR PANTHER; PTHR34339; PTHR34339; 1.
DR Pfam; PF15009; TMEM173; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Cytoplasm; Cytoplasmic vesicle; Endoplasmic reticulum;
KW Golgi apparatus; Immunity; Innate immunity; Lipoprotein; Membrane;
KW Mitochondrion; Mitochondrion outer membrane; Nucleotide-binding; Palmitate;
KW Phosphoprotein; Transmembrane; Transmembrane helix.
FT CHAIN 1..379
FT /note="Stimulator of interferon genes protein"
FT /id="PRO_0000455458"
FT TRANSMEM 20..40
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 87..107
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 115..135
FT /note="Helical"
FT /evidence="ECO:0000255"
FT REGION 153..340
FT /note="Cyclic dinucleotide-binding domain (CBD)"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT REGION 340..379
FT /note="C-terminal tail (CTT)"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT MOTIF 363..366
FT /note="pLxIS motif"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT BINDING 162
FT /ligand="2',3'-cGAMP"
FT /ligand_id="ChEBI:CHEBI:143093"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT BINDING 162
FT /ligand="cyclic di-3',5'-guanylate"
FT /ligand_id="ChEBI:CHEBI:58805"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT BINDING 167
FT /ligand="2',3'-cGAMP"
FT /ligand_id="ChEBI:CHEBI:143093"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT BINDING 167
FT /ligand="cyclic di-3',5'-guanylate"
FT /ligand_id="ChEBI:CHEBI:58805"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT BINDING 238..241
FT /ligand="cyclic di-3',5'-guanylate"
FT /ligand_id="ChEBI:CHEBI:58805"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT BINDING 238
FT /ligand="2',3'-cGAMP"
FT /ligand_id="ChEBI:CHEBI:143093"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT BINDING 263
FT /ligand="2',3'-cGAMP"
FT /ligand_id="ChEBI:CHEBI:143093"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT BINDING 263
FT /ligand="cyclic di-3',5'-guanylate"
FT /ligand_id="ChEBI:CHEBI:58805"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT SITE 358
FT /note="Not phosphorylated"
FT /evidence="ECO:0000269|PubMed:29478775"
FT MOD_RES 366
FT /note="Phosphoserine; by TBK1"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT LIPID 88
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000250|UniProtKB:Q3TBT3"
FT LIPID 91
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000250|UniProtKB:Q3TBT3"
FT MUTAGEN 358
FT /note="H->S: Restores STING1 abilty to induce a strong
FT inflammatory response, resulting in type-I interferons
FT activation and virus inhibition."
FT /evidence="ECO:0000269|PubMed:29478775"
SQ SEQUENCE 379 AA; 42537 MW; F392BBA318D12D37 CRC64;
MSHSSLHPSI PWPRGHKAKV AAFVLLIVCL AALWKLGEPS DHLLQWLVLH LASLHLRLLF
KRVCCLAEEL CHIHPRYQGN YSRAVRACLG CPIRYGAVLL LSCYFYVSLP NTVDLPLTWM
LAHLGLSEAL NILLGLQSLT PAEISTICEQ RNFNVAHGLA WSYYIGYLQL ILPGLRARIH
TYNQLHSNTL QGVGSHRLYI LFPLDCGVLD DLSAADPNIR FLHELPRQSA DRAGIKGRVY
TNSVYELLEK GKPVGTCVLE YATPLQTLFA MSQDGRAGFS QEDRLEQAKL FCRTLEDILA
DAPESQKNCR LIVYQEPTEE SDFSLSQEIL KHLRQEEREE VTMGTAGTFV APGSSTLHQE
PELLISGMDQ PLPLRTDIF
