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bioRxiv · 10.64898/2026.05.22.727066

HDAC6 and SSAT2 orchestrate acetyllysine metabolism and protein homeostasis

Wu, F.·Paramasivam, S.·Noonepalle, S.·Batushansky, A.·Vosahlikova, M.·Villagra, A.·Barinka, C.·Arbely, E.
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Abstract

Lysine acetylation is a prevalent and dynamic posttranslational modification, yet the metabolic fate and physiological role of free N {varepsilon}-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 {varepsilon}-acyl-lysine deacylase. AcK functions both as a recyclable lysine reservoir and as a signaling metabolite that elevates -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.

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Wu, F., Paramasivam, S., Noonepalle, S., Batushansky, A., Vosahlikova, M., Villagra, A., Barinka, C., Arbely, E.. 2026-05-26. HDAC6 and SSAT2 orchestrate acetyllysine metabolism and protein homeostasis. https://doi.org/10.64898/2026.05.22.727066

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