{"doi":"10.17615/5hmx-vs36","title":"The CATERPILLER Protein Monarch-1 Is an Antagonist of Toll-like Receptor-, Tumor Necrosis Factor α-, and Mycobacterium tuberculosis -induced Pro-inflammatory Signals","abstract":"The CATERPILLER (CLR, also NOD and NLR) proteins share structural similarities with the nucleotide binding domain (NBD)-leucine-rich repeat (LRR) superfamily of plant disease-resistance (R) proteins and are emerging as important immune regulators in animals. CLR proteins contain NBD-LRR motifs and are linked to a limited number of distinct N-terminal domains including transactivation, CARD (caspase activation and recruitment), and pyrin domains (PyD). The CLR gene, Monarch-1/Pypaf7, is expressed by resting primary myeloid/monocytic cells, and its expression in these cells is reduced by Toll-like receptor (TLR) agonists tumor necrosis factor (TNF) α and Mycobacterium tuberculosis. Monarch-1 reduces NFκB activation by TLR-signaling molecules MyD88, IRAK-1 (type I interleukin-1 receptor-associated protein kinase), and TRAF6 (TNF receptor (TNFR)-associated factor) as well as TNFR signaling molecules TRAF2 and RIP1 but not the downstream NFκB subunit p65. This indicates that Monarch-1 is a negative regulator of both TLR and TNFR pathways. Reducing Monarch-1 expression with small interference RNA in myeloid/ monocytic cells caused a dramatic increase in NFκB activation and cytokine expression in response to TLR2/TLR4 agonists, TNFα, or M. tuberculosis infection, suggesting that Monarch-1 is a negative regulator of inflammation. Because Monarch-1 is the first CLR protein that interferes with both TLR2 and TLR4 activation, the mechanism of this interference is significant. We find that Monarch-1 associates with IRAK-1 but not MyD88, resulting in the blockage of IRAK-1 hyperphosphorylation. Mutants containing the NBD-LRR or PyD-NBD also blocked IRAK-1 activation. This is the first example of a CLR protein that antagonizes inflammatory responses initiated by TLR agonists via interference with IRAK-1 activation.","journal":"UNC Libraries","year":2020,"id":141142,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9635,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":579833,"name":"John D. Lich","orcid":null,"position":1,"is_corresponding":false},{"id":320955,"name":"Christopher C. Moore","orcid":"0000-0001-6027-1732","position":2,"is_corresponding":false},{"id":548978,"name":"Kristi L. Williams","orcid":null,"position":3,"is_corresponding":false},{"id":266087,"name":"Stefanie N. Vogel","orcid":"0000-0001-8244-2555","position":4,"is_corresponding":false},{"id":255662,"name":"Lishan Su","orcid":"0000-0002-0350-5560","position":5,"is_corresponding":false},{"id":299129,"name":"Jenny P.‐Y. Ting","orcid":"0000-0002-7846-0395","position":6,"is_corresponding":false},{"id":446865,"name":"Sherry L. Kurtz","orcid":"0000-0002-2281-8984","position":7,"is_corresponding":false},{"id":543991,"name":"Miriam Braunstein","orcid":"0000-0003-1180-0030","position":8,"is_corresponding":false},{"id":579832,"name":"Prasad Rallabhandi","orcid":null,"position":9,"is_corresponding":false},{"id":579831,"name":"Mary Ann Accavitti-Loper","orcid":null,"position":10,"is_corresponding":false},{"id":579249,"name":"William Reed","orcid":"0009-0006-1662-4207","position":11,"is_corresponding":false},{"id":540046,"name":"Vernon M. Coffield","orcid":null,"position":12,"is_corresponding":false},{"id":277691,"name":"Joseph A. Duncan","orcid":"0000-0002-4438-2018","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:17:24.429854Z","pmid":null,"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":[]}