Ubiquitination by a Mycobacterium protein that mimics E1 and E3 activities

Mycobacterium tuberculosis (Mtb) has evolved various strategies to co-opt the host ubiquitin network to facilitate its proliferation. In the current issue of EMBO Reports, Liu and colleagues (Wang et al, 2021) demonstrate that the Mtb kinase PknG catalyzes ubiquitination by an unprecedented mechanism wherein the reaction starts by ATP hydrolysis occurring at the α-phosphate position, leading to covalent attachment of the modifier to Lys82 of the E2 conjugation enzyme UbcH7. Ubiquitin is then delivered to host proteins important for immunity by a putative peptidase activity also embedded in PknG. This novel activity of PknG expands our understanding of protein ubiquitination mechanisms, which may be harnessed to identify potential therapeutics for fighting Mtb infection.