Myeloid differentiation primary response protein 88 (MyD88) (MyD88)

Myeloid differentiation primary response protein 88 (MyD88) is a critical adapter protein that functions as a central hub for the innate immune system, mediating signal transduction for nearly all Toll-like receptors (TLRs), except TLR3, and the interleukin-1 receptor (IL-1R) family [UniProt P26367; Medzhitov et al., 1998, Mol Cell]. Upon ligand binding to these receptors, MyD88 is recruited to the receptor's cytoplasmic TIR domain, where it facilitates the assembly of the 'myddosome' complex consisting of IRAK family kinases [Lin et al., 2010, Nature]. This assembly triggers a signaling cascade that activates the transcription factor NF-κB and mitogen-activated protein kinases (MAPKs), leading to the expression of pro-inflammatory cytokines and survival genes [O'Neill & Bowie, 2007, Nat Rev Immunol]. In clinical contexts, the MYD88 L265P somatic mutation is a defining feature of Waldenström macroglobulinemia and is frequently found in activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), where it drives constitutive survival signaling [Treon et al., 2012, NEJM; Ngo et al., 2011, Nature]. Therapeutic interventions targeting MyD88 include small molecule inhibitors designed to block its dimerization and RNA-based strategies, such as antisense oligonucleotides (ASOs) or siRNA, which target MYD88 mRNA for degradation to prevent protein synthesis [Wang et al., 2020, Sig Transduct Target Ther; Ansell et al., 2014, Blood]. However, therapeutic inhibition of MyD88 carries a significant risk of increased susceptibility to invasive pyogenic bacterial infections, reflecting the protein's essential role in host defense [von Bernuth et al., 2008, Science].

Other names

MYD88Myeloid differentiation primary response 88MYD88D

Inhibition of the MyD88-dependent signaling pathway by preventing protein dimerization or by utilizing antisense oligonucleotides and siRNA to induce the degradation of MYD88 mRNA, thereby reducing protein expression and downstream NF-κB activation [Wang et al., 2020, Sig Transduct Target Ther; Ansell et al., 2014, Blood].