K63ketens

K63ketens, in full K63-linked ubiquitin chains, are polyubiquitin chains where ubiquitin molecules are linked through the lysine-63 residue. Unlike the more degradative K48-linked chains, K63ketens primarily act as signaling scaffolds that regulate cellular processes rather than marking proteins for proteasomal destruction. They are detected in a variety of eukaryotic cells and organisms and play roles in multiple pathways, including immune signaling, DNA damage response, endocytosis, and selective autophagy.

Formation and regulation occur through the ubiquitination cascade. The E1 activating enzyme, E2 conjugating enzymes, and E3 ubiquitin ligases cooperate to assemble K63-linked chains. A primary source of K63 linkage is the E2 enzyme complex Ubc13 in association with UEV1A or UEV1B, which preferentially builds K63 chains in concert with appropriate E3 ligases such as TRAF6, RNF8, or RNF168. Deubiquitinases, including AMSH, BRCC36, CYLD, and others, can remove K63 linkages, enabling dynamic control of signaling events.

Biological consequences of K63ketens are diverse. They act as molecular platforms that recruit signaling proteins to propagate pathways such as NF-κB and MAP kinase signaling, influencing inflammatory and immune responses. In the DNA damage response, K63 chains at double-strand break sites help assemble repair complexes, facilitating coordination of repair factors. In endocytosis, they regulate receptor trafficking, and in autophagy, they can mark damaged organelles or protein aggregates for clearance.

Dysregulation of K63ketens has been linked to diseases including cancer and inflammatory disorders, highlighting their importance in cell physiology. Research continues to elucidate the specific ligases and deubiquitinases that shape K63 signaling in different cellular contexts.