Kdm3a lysine demethylase is an Hsp90 client required for cytoskeletal rearrangements during spermatogenesis

Abstract

Chromatin remodeling enzymes can also have nonhistone roles, broadening their biological functions. It is shown that Kdm3a binding to cellular chaperones in the cytoplasm is relevant for morphogenetic events leading to infertility in enzymatically null mice. This provides evidence that Kdm3a is not just a histone modifier.

KDM3A coordinates actin dynamics with intraflagellar transport to regulate cilia stability

“…Interestingly, mouse mutants for the histone N-lysine demethylase Kdm3a (Jmjd1a, Tsga, or Jhdm2a) are obese, predisposed to diabetes (Inagaki et al, 2009;Tateishi et al, 2009), and have male infertility phenotypes (Okada et al, 2007) overlapping with mouse models of dysfunctional cilia. Structural abnormalities of the acrosome and manchette were observed in mutant Kdm3a mouse spermatids (Kasioulis et al, 2014) similar to those reported for conditional inactivation of Ift88 (Kierszenbaum, 2002;San Agustin et al, 2015). KDM3A localizes to the actin-rich acrosome-acroplaxome region, which is altered in Kdm3a mutant spermatids (Kasioulis et al, 2014).…”

“…Structural abnormalities of the acrosome and manchette were observed in mutant Kdm3a mouse spermatids (Kasioulis et al, 2014) similar to those reported for conditional inactivation of Ift88 (Kierszenbaum, 2002;San Agustin et al, 2015). KDM3A localizes to the actin-rich acrosome-acroplaxome region, which is altered in Kdm3a mutant spermatids (Kasioulis et al, 2014). In spite of these phenotypic and functional overlaps, a link between KDM3A and ciliogenesis has not been investigated.…”

“…More recently, scaffolding and noncatalytic modes of transcriptional regulation by KDM3A have emerged wherein KDM3A binds to the SWI-SNF (Switch-sucrose nonfermentable) chromatin-remodeling complex (Abe et al, 2015) or Hedgehog-responsive transcription factor GLI1 (Schneider et al, 2015), regulating expression of target genes. Although these functions relate to the role of KDM3A in the nucleus, KDM3A exits the nucleus in response to mechanosensitive stimuli (Kaukonen et al, 2016) and is found at various cytoplasmic sites of somatic cells and during germ cell development (Okada et al, 2007;Yang et al, 2009;Yamada et al, 2012;Kasioulis et al, 2014). Altogether, these findings indicate that KDM3A is a multifunctional protein with highly regulated subcellular distributions and nontranscriptional roles that remain to be explored.…”

HSP90AB1: Helping the good and the bad

“…Some effects of HSP90 on the cytoskeleton may be mediated by other proteins like the lysine demethylase Kdm3a. Mutant Kdm3a mice display male infertility and their cells show an altered fractionation of actin and tubulin (Kasioulis et al 2014). …”

The Emerging Role of Histone Demethylases in Renal Cell Carcinoma

“…KDM3A is also involved in other cellular processes such as cell cycle, embryonic and adult stem cell renewal, and differentiation of vascular smooth muscle (15). KDM3A has been implicated in the development and progression of several malignancies, including hepatocellular carcinoma and gastric cancer (16, 17).…”