Dual E2 ubiquitin-conjugating enzyme/E3 ubiquitin-protein ligase BIRC6

BIRC6 is a dual E2/E3 ubiquitin-conjugating enzyme that functions as an inhibitor of apoptosis by controlling caspase activity and ubiquitinating pro-apoptotic factors (UniProt: Q9NR09). Unlike canonical IAPs, it lacks a RING domain and instead combines E2 and E3 enzymatic activities within a single polypeptide, interacting with the non-canonical E1 enzyme UBA6 to ubiquitinate caspases 3, 7, and 9, as well as pro-apoptotic regulators DIABLO/SMAC and HTRA2. BIRC6 also regulates autophagy through MAP1LC3B ubiquitination and plays important roles in cytokinesis and midbody integrity.

In Alzheimer's disease, BIRC6 is significantly down-regulated in post-mortem AD brain tissue compared to age-matched controls (Chaparral AD proteomics; mean log2FC −0.52). This reduction in an anti-apoptotic protein may reflect increased neuronal cell death pathways in AD pathophysiology, potentially contributing to the neurodegeneration characteristic of the disease. The down-regulation was detected across subcellular fractions in TMT-labeled quantitative proteomic analysis of human brain tissue.