HDAC6 and SSAT2 orchestrate acetyllysine metabolism and protein homeostasis

Lysine acetylation is a prevalent and dynamic posttranslational modification, yet the metabolic fate and physiological role of free N ^ε -acetyl-L-lysine (AcK) remain unclear. Here, we identify opposing enzyme-catalyzed reactions linking lysine/AcK homeostasis to protein stability. We show that the first catalytic domain of HDAC6 stereospecifically deacetylates free AcK, establishing HDAC6 as an N ^ε -acyl-lysine deacylase. AcK functions both as a recyclable lysine reservoir and as a signaling metabolite that elevates α-tubulin acetylation and suppresses cell migration. Conversely, SSAT2 acetylates free lysine in cells and undergoes substrate-dependent C-terminal autoacetylation. We demonstrate that C-terminal lysine acetylation constitutes a reversible proteasomal degradation signal that promotes SSAT2 degradation and may extend to additional proteins bearing a terminal lysine. Stabilization of SSAT2 by HDAC6-dependent deacetylation, together with intricate regulation affected by substrate availability, reveals a novel mechanism that couples amino acid recycling to cytoskeletal dynamics and proteostasis.