{"doi":"10.1093/jimmun/vkaf217","title":"RACK1 is required for normal B cell development and signaling but not RAG1 degradation","abstract":"V(D)J recombination is constrained by timely degradation of the RAG1 and RAG2 proteins through distinct mechanisms. Previously, we showed that full-length RAG1 stability is regulated by viral protein R binding protein (VprBP) through its association with an amino-terminal region in RAG1, but the mechanism remains unclear. As an unbiased approach to uncover potential cofactors involved in the process, we compared protein interactomes between RAG1/RAG2 complexes formed when the amino-terminal third of RAG1 was present or absent. These experiments identified RACK1 as preferentially associating with full-length RAG1. Because RACK1 is implicated in mediating protein degradation in other contexts, we evaluated how loss of RACK1 in B cells affects B cell development and V(D)J recombination. We find that conditional disruption of Rack1 expression in the B lineage in mice blocks B cell development at the pro-B cell stage and impairs V(D)J recombination after Igh DH-JH rearrangement. In this background, enforced Bcl2 expression does not significantly rescue B cell development but does enable the V(D)J recombination defect to be bypassed. However, the phenotype of these mice does not show the excessive Igk rearrangement, skewing toward Igλ+ B cells, or increased RAG1 protein levels observed when VprBP expression is similarly disrupted in B cells, arguing against RACK1 serving as a cofactor in RAG1 degradation. Further studies provide evidence that loss of RACK1 in primary B cells dysregulates cell cycle progression, apoptosis, proliferation, and signaling through MAPK and NF-κB pathways.","journal":"The Journal of Immunology","year":2025,"id":546336,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9519,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":288571,"name":"N. Max Schabla","orcid":"0000-0002-0382-6444","position":1,"is_corresponding":false},{"id":320558,"name":"Vikas Kumar","orcid":"0000-0001-7513-6832","position":2,"is_corresponding":false},{"id":597475,"name":"Patrick C. Swanson","orcid":"0000-0002-3290-6582","position":3,"is_corresponding":false},{"id":597474,"name":"Victoria Palmer","orcid":"0000-0003-0507-8862","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-19T02:53:32.285899Z","pmid":"40849887","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":[]}