{"doi":"10.1371/journal.ppat.1010627","title":"Nucleocapsid mutations in SARS-CoV-2 augment replication and pathogenesis","abstract":"While SARS-CoV-2 continues to adapt for human infection and transmission, genetic variation outside of the spike gene remains largely unexplored. This study investigates a highly variable region at residues 203-205 in the SARS-CoV-2 nucleocapsid protein. Recreating a mutation found in the alpha and omicron variants in an early pandemic (WA-1) background, we find that the R203K+G204R mutation is sufficient to enhance replication, fitness, and pathogenesis of SARS-CoV-2. The R203K+G204R mutant corresponds with increased viral RNA and protein both in vitro and in vivo. Importantly, the R203K+G204R mutation increases nucleocapsid phosphorylation and confers resistance to inhibition of the GSK-3 kinase, providing a molecular basis for increased virus replication. Notably, analogous alanine substitutions at positions 203+204 also increase SARS-CoV-2 replication and augment phosphorylation, suggesting that infection is enhanced through ablation of the ancestral 'RG' motif. Overall, these results demonstrate that variant mutations outside spike are key components in SARS-CoV-2's continued adaptation to human infection.","journal":"PLoS Pathogens","year":2022,"id":232735,"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":169,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9568,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":275507,"name":"Yiyang Zhou","orcid":"0000-0001-8956-3229","position":1,"is_corresponding":false},{"id":105305,"name":"Kumari G. Lokugamage","orcid":null,"position":2,"is_corresponding":false},{"id":550017,"name":"Michelle N. Vu","orcid":"0000-0002-3208-710X","position":3,"is_corresponding":false},{"id":108476,"name":"Nathen E. Bopp","orcid":null,"position":4,"is_corresponding":false},{"id":641735,"name":"Patricia A. Crocquet-Valdes","orcid":"0000-0002-2079-0076","position":5,"is_corresponding":false},{"id":105314,"name":"Birte Kalveram","orcid":null,"position":6,"is_corresponding":false},{"id":108475,"name":"Craig Schindewolf","orcid":"0000-0002-9804-2246","position":7,"is_corresponding":false},{"id":560681,"name":"Yang Liu","orcid":"0000-0002-1109-0756","position":8,"is_corresponding":false},{"id":105310,"name":"Dionna Scharton","orcid":"0000-0002-5919-3922","position":9,"is_corresponding":false},{"id":105300,"name":"Jessica A. Plante","orcid":"0000-0002-4768-7458","position":10,"is_corresponding":false},{"id":105317,"name":"Xuping Xie","orcid":"0000-0003-0918-016X","position":11,"is_corresponding":false},{"id":551105,"name":"Patricia Aguilar","orcid":null,"position":12,"is_corresponding":false},{"id":105319,"name":"Scott C. Weaver","orcid":"0000-0001-8016-8556","position":13,"is_corresponding":false},{"id":38215,"name":"Pei‐Yong Shi","orcid":"0000-0001-5553-1616","position":14,"is_corresponding":false},{"id":439576,"name":"David H. Walker","orcid":"0000-0002-3309-4360","position":15,"is_corresponding":false},{"id":275508,"name":"Andrew Routh","orcid":"0000-0002-2874-5990","position":16,"is_corresponding":false},{"id":105318,"name":"Kenneth S. Plante","orcid":"0000-0002-7485-3167","position":17,"is_corresponding":false},{"id":105316,"name":"Vineet D. Menachery","orcid":"0000-0001-8803-7606","position":18,"is_corresponding":false},{"id":105304,"name":"Bryan A. Johnson","orcid":"0000-0002-8999-1255","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T00:21:18.683916Z","pmid":"35728038","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":[]}