Ubiquitin chains linked through lysine63 (K63) play a critical role in inflammatory signalling. Following ligand engagement of immune receptors, the RING E3 ligase TRAF6 builds K63-linked chains together with the heterodimeric E2 enzyme Ubc13-Uev1A. Dimerisation of the TRAF6 RING domain is essential for the assembly of K63-linked ubiquitin chains. Here, we show that TRAF6 RING dimers form a catalytic complex where one RING interacts with a Ubc13~Ubiquitin conjugate, while the zinc finger 1 (ZF1) domain and linker-helix of the opposing monomer contact ubiquitin. The RING dimer interface is conserved across TRAFs and we also show that TRAF5–TRAF6 heterodimers form. Importantly, TRAF5 can provide ZF1, enabling ubiquitin transfer from a TRAF6-bound Ubc13 conjugate. Our study explains the dependence of activity on TRAF RING dimers, and suggests that both homo- and heterodimers mediated by TRAF RING domains have the capacity to synthesise ubiquitin chains.

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For many inflammatory cytokines, the response elicited is dependent on the recruitment of the tumour necrosis factor receptor‐associated factor (TRAF) family of adaptor proteins. All TRAF proteins have a trimeric C‐terminal TRAF domain, while at the N‐terminus most TRAFs have a RING domain that forms dimers. The symmetry mismatch of the N‐ and C‐terminal halves of TRAF proteins means that when receptors cluster, it is presumed that RING dimers connect TRAF trimers to form a network. Here, using purified TRAF6 proteins, we provide direct evidence in support of this model, and we show that TRAF6 trimers bind Lys63‐linked ubiquitin chains to promote their processive assembly. This study provides critical evidence in support of TRAF trimers as key players in signalling.

Leprosy is a chronic mycobacterial infection that elicits an extraordinary range of cellular immune responses in humans. Leprosy is also known as Hansen's disease after GA Hansen who discovered it in 1873. The infection is curable but not preventable, and remains a major global health problem, especially in the developing world. Complex segregation analysis study suggests an oligogenic model of leprosy susceptibility stating that the patients carry susceptible allele's loci. The infection in humans is influenced by genetic variation (SNPs) in the associated genes, that is, genes that contribute to the innate immune recognition of mycobacteria. Recognition of mycobacteria by the adaptive immune system, involves products of human leucocyte antigen/major histocompatibility complex genes and effector responses of the immune system. Host genetics plays an important role in determining an individual's risk of developing clinical leprosy. Host susceptibility genetic susceptibility to leprosy is complicated by the genetics of Mycobacterium leprae , interaction between gene and environmental factors, gene–gene interactions and lastly ethnicity. The host immune response influences the course of infection (host–pathogen relationship) and provides an exciting challenge to understand the genetics of disease susceptibility and immunopathogenesis of leprosy. Key Concepts: Leprosy was identified as the first devastating disease of humans causing disability by the bacterial pathogen Mycobacterium leprae . Genomic data might be useful in the development of drugs and vaccines against leprosy. Despite widespread implementation of effective multidrug therapy, leprosy has not been eliminated. Complex segregation analyses have suggested a predominant genetic rather than environmental model for associations in leprosy. Recognition of mycobacteria by the adaptive immune system involving products of human leucocyte antigen/major histocompatibility complex genes and effector responses of the immune system (genes affecting cytokines, chemokines and immunomodulators). Direct involvement of SNPs in different genes in host genetic susceptibility to leprosy. Single nucleotide polymorphisms (SNPs) represent an important class of genetic variation, and SNPs within and outside coding sequences are under intense examination for possible associations or mechanistic links to disease. Haplotypes are combinations of two or more polymorphisms (SNPs in this case) within a single chromosome in an individual, which can be used as genetic markers. The availability of the M . leprae genome sequence and improved methodologies for molecular level diagnosis of the genetic basis of drug resistance in mycobacteria led to the development of molecular methods for drug‐susceptibility testing (DST).