{"doi":"10.1016/j.jbc.2021.100991","title":"Deletion of mFICD AMPylase alters cytokine secretion and affects visual short-term learning in vivo","abstract":"Fic domain-containing AMP transferases (fic AMPylases) are conserved enzymes that catalyze the covalent transfer of AMP to proteins. This posttranslational modification regulates the function of several proteins, including the ER-resident chaperone Grp78/BiP. Here we introduce a mouse FICD (mFICD) AMPylase knockout mouse model to study fic AMPylase function in vertebrates. We find that mFICD deficiency is well tolerated in unstressed mice. We also show that mFICD-deficient mouse embryonic fibroblasts are depleted of AMPylated proteins. mFICD deletion alters protein synthesis and secretion in splenocytes, including that of IgM, an antibody secreted early during infections, and the proinflammatory cytokine IL-1β, without affecting the unfolded protein response. Finally, we demonstrate that visual nonspatial short-term learning is stronger in old mFICD−/− mice than in wild-type controls while other measures of cognition, memory, and learning are unaffected. Together, our results suggest a role for mFICD in adaptive immunity and neuronal plasticity in vivo. Fic domain-containing AMP transferases (fic AMPylases) are conserved enzymes that catalyze the covalent transfer of AMP to proteins. This posttranslational modification regulates the function of several proteins, including the ER-resident chaperone Grp78/BiP. Here we introduce a mouse FICD (mFICD) AMPylase knockout mouse model to study fic AMPylase function in vertebrates. We find that mFICD deficiency is well tolerated in unstressed mice. We also show that mFICD-deficient mouse embryonic fibroblasts are depleted of AMPylated proteins. mFICD deletion alters protein synthesis and secretion in splenocytes, including that of IgM, an antibody secreted early during infections, and the proinflammatory cytokine IL-1β, without affecting the unfolded protein response. Finally, we demonstrate that visual nonspatial short-term learning is stronger in old mFICD−/− mice than in wild-type controls while other measures of cognition, memory, and learning are unaffected. Together, our results suggest a role for mFICD in adaptive immunity and neuronal plasticity in vivo. The posttranslational regulation of protein function is a fundamental concept in biology. To manage protein activity, dedicated enzymes attach specific chemical modifications to individual proteins, the presence of which affects the behavior and activity of the modified proteins. These modifications, called posttranslational modifications (PTMs), govern essential biological processes. They are implicated in cancer, neurodegeneration, and cardiovascular diseases, among others. The covalent addition of an AMP moiety to the side chain of exposed threonine and serine residues has emerged as a new paradigm to control the activity of the essential ER-resident chaperone BiP. This process, AMPylation, is catalyzed by metazoan AMP transferases (AMPylases) that contain a filamentation induced by c-AMP (fic) domain. Fic domain-containing AMPylases (fic AMPylases) are highly conserved and are present in a single copy in most metazoans, including Caenorhabditis elegans (FIC-1), Drosophila melanogaster (dfic), Mus musculus (mFICD), and Homo sapiens (FICD) (1Woolery A.R. Luong P. Broberg C.A. Orth K. AMPylation: Something old is new again.Front. Microbiol. 2010; 1: 113Crossref PubMed Scopus (51) Google Scholar, 2Itzen A. Blankenfeldt W. Goody R.S. Adenylylation: Renaissance of a forgotten post-translational modification.Trends Biochem. Sci. 2011; 36: 221-228Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar, 3Truttmann M.C.P.H.L. rAMPing up stress signaling: Protein AMPylation in metazoans.Trends Cell Biol. 2017; 27: 608-620Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar). Metazoan fic AMPylases are bifunctional: using a single active site, these enzymes catalyze both the transfer of AMP to surface-exposed threonine and serine hydroxyl groups and the removal of AMP groups from modified residues (deAMPylation)","journal":"Journal of Biological Chemistry","year":2021,"id":175664,"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":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9496,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":716909,"name":"Corey M. Porter","orcid":"0000-0001-9095-9984","position":1,"is_corresponding":false},{"id":716910,"name":"Anouk M.D. Becker","orcid":"0000-0002-4758-9030","position":2,"is_corresponding":false},{"id":289731,"name":"Chih-Hang Anthony Tang","orcid":"0000-0002-5097-5709","position":3,"is_corresponding":false},{"id":283307,"name":"Charlotte Wijne","orcid":null,"position":4,"is_corresponding":false},{"id":716911,"name":"Bhaskar K. Chatterjee","orcid":"0000-0003-2626-5763","position":5,"is_corresponding":false},{"id":535259,"name":"Djenet Bousbaine","orcid":"0000-0003-2683-9544","position":6,"is_corresponding":false},{"id":295160,"name":"Angelina M. Bilate","orcid":"0000-0003-4575-786X","position":7,"is_corresponding":false},{"id":289732,"name":"Chih‐Chi Andrew Hu","orcid":"0000-0001-9024-2932","position":8,"is_corresponding":false},{"id":245647,"name":"Hidde L. Ploegh","orcid":"0000-0002-1090-6071","position":9,"is_corresponding":false},{"id":716912,"name":"Matthias C. Truttmann","orcid":"0000-0002-0536-7923","position":10,"is_corresponding":false},{"id":690536,"name":"Nicholas McCaul","orcid":"0000-0002-7888-7815","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-18T23:47:15.431199Z","pmid":"34419450","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":[]}