The MYND domain-containing protein BRAM1 inhibits lymphotoxin beta receptor-mediated signaling through affecting receptor oligomerization.
MYND (myeloid-Nervy-DEAF-1) domains exist in a large number of proteins that are functionally important in development or associated with cancers. We have previously demonstrated that a MYND domain-containing protein, the bone morphogenesis protein receptor-associated molecule 1 (BRAM1), is able to interact with Epstein-Barr virus-encoded latent membrane protein 1 (LMP1), which ... acts as a constitutively activated tumor necrosis factor receptor (TNFR). Herein we further demonstrated that BRAM1 additionally associates with the TNFR-superfamily member, the lymphotoxin beta receptor (LTβR), and hence inhibits LTβR-mediated function. Using the yeast two-hybrid assay, we demonstrated that BRAM1 interacts with LTβR mainly through the self-association domain of LTβR (aa 336-398). The co-immunoprecipitation experiment further revealed that BRAM1 as well as MYND domain-containing proteins, MTG8 and DEAF-1, interacts with LTβR via their MYND domains. The BRAM1-LTβR interaction impedes the self-association of LTβR and the recruitment of TNFR-associated factors 2 and 3 (TRAF2 and TRAF3), leading to abolishment of LTβR-induced NF-κB signaling, JNK activation, and caspase-dependent cell death. In sum, our data demonstrate that the MYND-containing protein BRAM1 abrogates LTβR function through a protein-protein interaction. These findings may provide a direction for the treatment of dysregulation of LTβR-mediated signaling.
Mesh Terms:
Apoptosis, Carrier Proteins, Caspases, Cell Line, Humans, Immunoprecipitation, JNK Mitogen-Activated Protein Kinases, Lymphotoxin beta Receptor, NF-kappa B, Protein Binding, Protein Structure, Tertiary, Receptors, Tumor Necrosis Factor, Signal Transduction, TNF Receptor-Associated Factor 2, TNF Receptor-Associated Factor 3, Two-Hybrid System Techniques
Apoptosis, Carrier Proteins, Caspases, Cell Line, Humans, Immunoprecipitation, JNK Mitogen-Activated Protein Kinases, Lymphotoxin beta Receptor, NF-kappa B, Protein Binding, Protein Structure, Tertiary, Receptors, Tumor Necrosis Factor, Signal Transduction, TNF Receptor-Associated Factor 2, TNF Receptor-Associated Factor 3, Two-Hybrid System Techniques
Cell. Signal.
Date: Jan. 01, 2011
PubMed ID: 20732415
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