{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Yu X"],"funding":["NCRR NIH HHS","NIEHS NIH HHS"],"pagination":["1615-1627"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC7995293"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["137(12)"],"pubmed_abstract":["Myeloid differentiation primary response protein 88 (MYD88) is a critical universal adapter that transduces signaling from Toll-like and interleukin receptors to downstream nuclear factor-κB (NF-κB). MYD88L265P (leucine changed to proline at position 265) is a gain-of-function mutation that occurs frequently in B-cell malignancies such as Waldenstrom macroglobulinemia. In this study, E3 ligase RING finger protein family 138 (RNF138) catalyzed K63-linked nonproteolytic polyubiquitination of MYD88L265P, resulting in enhanced recruitment of interleukin-1 receptor-associated kinases and elevated NF-κB activation. However, RNF138 had little effect on wild-type MYD88 (MYD88WT). With either RNF138 knockdown or mutation on MYD88 ubiquitination sites, MYD88L265P did not constitutively activate NF-κB. A20, a negative regulator of NF-κB signaling, mediated K48-linked polyubiquitination of RNF138 for proteasomal degradation. Depletion of A20 further augmented MYD88L265P-mediated NF-κB activation and lymphoma growth. Furthermore, A20 expression correlated negatively with RNF138 expression and NF-κB activation in lymphomas with MYD88L265P and in those without. Strikingly, RNF138 expression correlated positively with NF-κB activation in lymphomas with MYD88L265P, but not in those without it. Our study revealed a novel mutation-specific biochemical reaction that drives B-cell oncogenesis, providing a therapeutic opportunity for targeting oncogenic MYD88L265P, while sparing MYD88WT, which is critical to innate immunity."],"journal":["Blood"],"pubmed_title":["MYD88 L265P elicits mutation-specific ubiquitination to drive NF-κB activation and lymphomagenesis."],"pmcid":["PMC7995293"],"funding_grant_id":["P42 ES027725","S10 RR031537"],"pubmed_authors":["Liu H","Young KH","Deng Q","Lu Z","Xu-Monette ZY","Zhang M","Li L","Li W","Li Y","Hu H","Cao Y","Wang X","Yu X"],"additional_accession":[]},"is_claimable":false,"name":"MYD88 L265P elicits mutation-specific ubiquitination to drive NF-κB activation and lymphomagenesis.","description":"Myeloid differentiation primary response protein 88 (MYD88) is a critical universal adapter that transduces signaling from Toll-like and interleukin receptors to downstream nuclear factor-κB (NF-κB). MYD88L265P (leucine changed to proline at position 265) is a gain-of-function mutation that occurs frequently in B-cell malignancies such as Waldenstrom macroglobulinemia. In this study, E3 ligase RING finger protein family 138 (RNF138) catalyzed K63-linked nonproteolytic polyubiquitination of MYD88L265P, resulting in enhanced recruitment of interleukin-1 receptor-associated kinases and elevated NF-κB activation. However, RNF138 had little effect on wild-type MYD88 (MYD88WT). With either RNF138 knockdown or mutation on MYD88 ubiquitination sites, MYD88L265P did not constitutively activate NF-κB. A20, a negative regulator of NF-κB signaling, mediated K48-linked polyubiquitination of RNF138 for proteasomal degradation. Depletion of A20 further augmented MYD88L265P-mediated NF-κB activation and lymphoma growth. Furthermore, A20 expression correlated negatively with RNF138 expression and NF-κB activation in lymphomas with MYD88L265P and in those without. Strikingly, RNF138 expression correlated positively with NF-κB activation in lymphomas with MYD88L265P, but not in those without it. Our study revealed a novel mutation-specific biochemical reaction that drives B-cell oncogenesis, providing a therapeutic opportunity for targeting oncogenic MYD88L265P, while sparing MYD88WT, which is critical to innate immunity.","dates":{"release":"2021-01-01T00:00:00Z","publication":"2021 Mar","modification":"2026-06-04T04:32:38.018Z","creation":"2025-04-06T21:50:24.137Z"},"accession":"S-EPMC7995293","cross_references":{"pubmed":["33025009"],"doi":["10.1182/blood.2020004918"]}}