KDM6A is enzymatically active at the Golgi apparatus where it is necessary for maintenance of Golgi apparatus morphology

Worth, C. S.; Conforti, J. M.; Nambiar, A. M.; Malone, J.; Budhathoki, R.; Ziegler, A. M.; Polavarapu, K.; Lilley, H.; Climer, L.; Simmons, D. D.; Kelber, J.; Gallagher, E. S.; Taube, J.

doi:10.64898/2026.11.02.763691

bioRxiv · 10.64898/2026.11.02.763691

KDM6A is enzymatically active at the Golgi apparatus where it is necessary for maintenance of Golgi apparatus morphology

Worth, C. S.·Conforti, J. M.·Nambiar, A. M.·Malone, J.·Budhathoki, R.·Ziegler, A. M.·Polavarapu, K.·Lilley, H.·Climer, L.·Simmons, D. D.·Kelber, J.·Gallagher, E. S.·Taube, J.

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Abstract

KDM6A and KDM6B, lysine demethylases, play a central role in regulation of transcription through their demethylation activity towards H3K27me3 and have also been shown to be dynamically regulated upon epithelial-mesenchymal transition (EMT). In particular, KDM6A has been implicated in a variety of malignancies and is frequently mutated in cancers including those in kidney, bladder, colorectal, and breast. KDM6A and KDM6B function as part of the COMPASS-like protein complex (CLC) which includes methyltransferases KMT2C/KMT2D and the regulatory WRAD-subcomplex. KDM6A total protein is known to be suppressed by TGF-{beta} in MCF10A breast cells; however, our examination of protein localization by immunofluorescence and LC-MS/MS reveals that KDM6A expression is lost in the nucleus but retained in the Golgi apparatus, independent of other CLC complex members. Importantly, KDM6A isolated from a biochemically-separated subcellular membranous fraction possesses the catalytic JmjC domain and is enzymatically active, indicating that KDM6A may have non-nuclear substrates. Further, knockdown of KDM6A and treatment with TGF-{beta} similarly alter Golgi apparatus morphology, in a cell type specific manner, suggesting context-dependent regulatory functions. These findings support a model in which KDM6A is necessary to maintain Golgi apparatus morphology and is enzymatically active outside of the nucleus.

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Worth, C. S., Conforti, J. M., Nambiar, A. M., Malone, J., Budhathoki, R., Ziegler, A. M., Polavarapu, K., Lilley, H., Climer, L., Simmons, D. D., Kelber, J., Gallagher, E. S., Taube, J.. 2026-11-04. KDM6A is enzymatically active at the Golgi apparatus where it is necessary for maintenance of Golgi apparatus morphology. https://doi.org/10.64898/2026.11.02.763691

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