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Biology subjects

Listovsky, T.

Publications and source records attributed to Listovsky, T..

2 recordsLinked to original sources
bioRxiv2026

SETDB1 promotes tubulin deacetylation and Golgi fragmentation by HDAC6

Microtubules (MTs) are dynamic cytoskeletal structures essential for intracellular transport, cell division, and organelle positioning. Their functions are regulated by post-translational modifications, including -tubulin acetylation at Lys40, which enhances MT stability and resilience. Histone deacetylase 6 (HDAC6) is the primary enzyme that reverses this modification, but its access to the luminal Lys40 residue is restricted. Previously, we identified SETDB1, a histone methyltransferase and known oncogene, as a cytoplasmic regulator of MT dynamics, attenuating MT polymerization and destabilizing MTs. Here, we uncover the molecular mechanism by which SETDB1 destabilizes MTs. SETDB1 interacts with HDAC6 and promotes its tubulin deacetylation activity. Mechanistically, SETDB1 enhances HDAC6 recruitment to polymerized MTs and induces repairable damage along MT shafts, generating entry points for HDAC6 into the MT lumen. Functionally, this axis regulates Golgi organization: SETDB1 overexpression disperses the Golgi in an HDAC6-dependent manner, while SETDB1 knockdown or HDAC6 inhibition compacts it. Notably, SETDB1s role in Golgi regulation is independent of its methyltransferase activity. These findings reveal crosstalk among the histone methylation machinery, MT dynamics, and Golgi organization. Since Golgi dispersal is thought to promote tumorigenesis, our results suggest that the SETDB1-HDAC6 axis is a potential therapeutic target. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/734187v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1857973org.highwire.dtl.DTLVardef@1e8a73eorg.highwire.dtl.DTLVardef@13c11deorg.highwire.dtl.DTLVardef@b937b1_HPS_FORMAT_FIGEXP M_FIG C_FIG

Cell Biology↗
bioRxiv2021

SETDB1 regulates microtubule dynamics

SETDB1 is a methyltransferase responsible for the methylation of histone H3-lysine-9, which is mainly related to heterochromatin formation. SETDB1 is overexpressed in various cancer types and is associated with an aggressive phenotype. In agreement with its activity, it mainly exhibits a nuclear localization; however, in several cell types a cytoplasmic localization was reported. Here we show that a substantial cytoplasmic pool of SETDB1 is colocalized with microtubules. Significantly, silencing of SETDB1 led to faster polymerization and reduced rate of catastrophe events of microtubules in parallel to reduced proliferation rate and slower mitotic kinetics. Interestingly, over-expression of either wild-type or catalytic dead SETDB1 altered microtubule polymerization rate to the same extent, suggesting that SETDB1 affects MT dynamics by a methylation-independent mechanism. Finding interaction between SETDB1 and the tubulin deacetylase HDAC6 and increased tubulin acetylation levels upon silencing of SETDB1 suggest a model in which SETDB1 affects microtubule dynamics by interacting with both microtubules and HDAC6 to enhance tubulin deacetylation. Overall, our results suggest a novel cytoplasmic role for SETDB1 in the regulation of microtubule dynamics.

cell biology↗