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 (LT beta R), and hence inhibits LT beta R-mediated function. Using the yeast two-hybrid assay, we demonstrated that BRAM] interacts with LT beta R mainly through the self-association domain of LT beta R (aa 336-398). The co-immunoprecipitation experiment further revealed that BRAM1 as well as MYND domain-containing proteins. MTG8 and DEAF-1, interacts with UDR via their MYND domains. The BRAM1-LT beta R interaction impedes the self-association of LT beta R and the recruitment of TNFR-associated factors 2 and 3 (TRAF2 and TRAF3), leading to abolishment of LT beta R-induced NF-kappa B signaling, JNK activation, and caspase-dependent cell death. In sum, our data demonstrate that the MYND-containing protein BRAM1 abrogates LT beta R function through a protein-protein interaction. These findings may provide a direction for the treatment of dysregulation of LT beta R-mediated signaling. (C) 2010 Elsevier Inc. All rights reserved.