A protein adaptor mediating Ap4A-dependent control of protein acetylation
- Liujuan Zheng
- Megan K. M. Young
- Wieland Steinchen
- Zhiyong Guo
- Ekaterina Jalomo-Khayrova
- Bobby Xuanyu Liu
- Fabiana Burchert
- Patricia Bedrunka
- Christopher-Nils Mais
- Jan Pané-Farré
- Mathias Girbig
- Uwe Linne
- Aude Trinquier
- Aitao Li
- Georg Hochberg
- Johannes Freitag
- Jue D. Wang
- Gert Bange
2026-02-23
Reversible lysine acetylation is a highly conserved post-translational modification across all domains of life controlling diverse cellular processes such as metabolism and gene expression. However, the regulation of protein acetylation remains poorly understood. Here, we report a regulatory system in Bacillus subtilis that controls the activity of the histone deacetylase (HDAC)-like protein AcuC, which has multiple substrates including acetyl-CoA synthetase and translation elongation factor. We show that AcuC is inhibited via formation of a stable complex with the hitherto uncharacterized protein AcuB. We furthermore demonstrate that the alarmone diadenosine tetraphosphate (Ap4A) binds to the cystathionine beta-synthase (CBS) domain of AcuB, thereby stabilizing AcuB and further enhancing the inhibition of AcuC. In summary, this study identifies AcuB as an Ap4A regulated deacetylation inhibitor, revealing a uncharacterized molecular mechanism to control HDAC-like proteins. Thus, the alarmone Ap4A modulates protein (de)acetylation, pointing towards a regulatory network that connects stress response, protein acetylation, and acetyl-CoA biosynthesis.