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Biology subjects

Dank, C.

Publications and source records attributed to Dank, C..

2 recordsLinked to original sources

ATG8ylation of vacuolar membrane protects plants against cell wall damage

Vacuoles are essential for cellular metabolism, growth, and the maintenance of internal turgor pressure. They sequester lytic enzymes, ions, and secondary metabolites that, if leaked into the cytosol, could lead to cell death. Despite their pivotal roles, quality control pathways that safeguard vacuolar integrity remained elusive in plants. Here, we discovered a conserved vacuolar quality control (VQC) pathway that is activated upon cell wall damage in a turgor pressure dependent manner. Cell wall perturbations induce a distinct modification - ATG8ylation - on the vacuolar membrane (tonoplast) that is regulated by the V-ATPase and ATG8 conjugation machinery. Genetic disruption of tonoplast ATG8ylation impairs vacuolar integrity, leading to cell death. Together, our findings reveal a homeostatic pathway that preserves vacuolar integrity upon cell wall damage.

plant biology↗

Discovery and characterization of a chemical probe targeting the zinc-finger ubiquitin-binding domain of HDAC6

Histone deacetylase 6 (HDAC6) inhibition is an attractive strategy for treating numerous cancers, and HDAC6 catalytic inhibitors are currently in clinical trials. The HDAC6 zinc-finger ubiquitin-binding domain (UBD) binds free C-terminal diglycine motifs of unanchored ubiquitin polymer chains and protein aggregates, playing an important role in autophagy and aggresome assembly. However, targeting this domain with small molecule antagonists remains an underdeveloped avenue of HDAC6-focused drug discovery. We report SGC-UBD253 (25), a chemical probe potently targeting HDAC6-UBD in vitro with selectivity over nine other UBDs, except for weak USP16 binding. In cells, 25 is an effective antagonist of HDAC6-UBD at 1 {micro}M, with marked proteome-wide selectivity. We identified SGC-UBD253N (32), a methylated derivative of 25 which is 300-fold less active, serving as a negative control. Together, 25 and 32 could enable further exploration of the biological function of the HDAC6 UBD and investigation of the therapeutic potential of targeting this domain.

pharmacology and toxicology↗