{"doi":"10.1101/2024.02.14.580367","title":"A single amino acid in the <i>Salmonella</i> effector SarA/SteE triggers supraphysiological activation of STAT3 for anti-inflammatory target gene expression","abstract":"Summary Non-typhoidal Salmonella enterica cause an estimated 1 million cases of gastroenteritis annually in the United States. These serovars use secreted protein effectors to mimic and reprogram host cellular functions. We previously discovered that the secreted effector SarA ( Salmonella anti-inflammatory response activator; also known as SteE) was required for increased intracellular replication of S. Typhimurium and production of the anti-inflammatory cytokine interleukin-10 (IL-10). SarA facilitates phosphorylation of STAT3 through a region of homology with the host cytokine receptor gp130. Here, we demonstrate that a single amino acid difference between SarA and gp130 is critical for the anti-inflammatory bias of SarA-STAT3 signaling. An isoleucine at the pY+1 position of the YxxQ motif in SarA (which binds the SH2 domain in STAT3) causes increased STAT3 phosphorylation and expression of anti-inflammatory target genes. This isoleucine, completely conserved in ∼4000 Salmonella isolates, renders SarA a better substrate for tyrosine phosphorylation by GSK-3. GSK-3 is canonically a serine/threonine kinase that nonetheless undergoes tyrosine autophosphorylation at a motif that has an invariant isoleucine at the pY+1 position. Our results provide a molecular basis for how a Salmonella secreted effector achieves supraphysiological levels of STAT3 activation to control host genes during infection.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":487930,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9591,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1332509,"name":"Angela G. Jones","orcid":"0000-0003-1096-8317","position":1,"is_corresponding":false},{"id":1332782,"name":"Ioanna Panagi","orcid":null,"position":2,"is_corresponding":false},{"id":383609,"name":"E. Washington","orcid":"0000-0002-7503-6492","position":3,"is_corresponding":false},{"id":1332510,"name":"Rachel E. Loney","orcid":"0000-0002-2872-4903","position":4,"is_corresponding":false},{"id":1332511,"name":"Janina H. Muench","orcid":"0000-0001-5838-9854","position":5,"is_corresponding":false},{"id":471385,"name":"Richard G. Brennan","orcid":"0000-0001-7647-485X","position":6,"is_corresponding":false},{"id":1287009,"name":"Teresa L. M. Thurston","orcid":"0000-0001-6139-3723","position":7,"is_corresponding":false},{"id":411019,"name":"Dennis C. Ko","orcid":"0000-0002-0113-5981","position":8,"is_corresponding":false},{"id":723044,"name":"Margaret R. Gaggioli","orcid":"0000-0002-6500-3996","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T02:08:15.008850Z","pmid":"38405869","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}