45 research outputs found
CYLD in Ubiquitin Signaling and Tumor Pathogenesis
Absence of CYLD, which encodes a deubiquitinating enzyme, causes an inherited disease characterized by benign skin tumors. In this issue of Cell, Massoumi et al. (2006) show that CYLD deubiquitinates the coactivator Bcl-3, thereby preventing its translocation into the nucleus, where it normally interacts with NF-ÎșB and activates transcription of proliferation genes in response to growth signals
Specific Recognition of Linear Ubiquitin Chains by NEMO Is Important for NF-ÎșB Activation
Activation of nuclear factor-ÎșB (NF-ÎșB), a key mediator of inducible transcription in immunity, requires binding of NF-ÎșB essential modulator (NEMO) to ubiquitinated substrates. Here, we report that the UBAN (ubiquitin binding in ABIN and NEMO) motif of NEMO selectively binds linear (head-to-tail) ubiquitin chains. Crystal structures of the UBAN motif revealed a parallel coiled-coil dimer that formed a heterotetrameric complex with two linear diubiquitin molecules. The UBAN dimer contacted all four ubiquitin moieties, and the integrity of each binding site was required for efficient NF-ÎșB activation. Binding occurred via a surface on the proximal ubiquitin moiety and the canonical Ile44 surface on the distal one, thereby providing specificity for linear chain recognition. Residues of NEMO involved in binding linear ubiquitin chains are required for NF-ÎșB activation by TNF-α and other agonists, providing an explanation for the detrimental effect of NEMO mutations in patients suffering from X-linked ectodermal dysplasia and immunodeficiency
The anti-apoptotic ubiquitin conjugating enzyme BIRC6/BRUCE regulates autophagosome-lysosome fusion
Linear Ubiquitin Chain-Binding Domains
Ubiquitin modification (ubiquitination) of target proteins can vary with respect to chain lengths, linkage type, and chain forms, such as homologous, mixed, and branched ubiquitin chains. Thus, ubiquitination can generate multiple unique surfaces on a target protein substrate. Ubiquitinâbinding domains (UBDs) recognize ubiquitinated substrates, by specifically binding to these unique surfaces, modulate the formation of cellular signaling complexes and regulate downstream signaling cascades. Among the eight different homotypic chain types, Met1âlinked (also termed linear) chains are the only chains in which linkage occurs on a nonâLys residue of ubiquitin. Linear ubiquitin chains have been implicated in immune responses, cell death and autophagy, and several UBDs â specific for linear ubiquitin chains â have been identified. In this review, we describe the main principles of ubiquitin recognition by UBDs, focusing on linear ubiquitin chains and their roles in biology
What Determines the Specificity and Outcomes of Ubiquitin Signaling?
Ubiquitin signals and ubiquitin-binding domains are implicated in almost every cellular process, but how is their functionality achieved in cells? We assess recent advances in monitoring the dynamics and specificity of ubiquitin networks in vivo and discuss challenges ahead.PaperCli