Phosphorylation of H3-Thr3 by Haspin Is Required for Primary Cilia Regulation

• Published in: International journal of molecular sciences 2021-07, Vol.22 (14), p.7753
• Main Authors: Quadri, Roberto, Sertic, Sarah, Ghilardi, Anna, Rondelli, Diego, Gallo, Guido Roberto, Del Giacco, Luca, Muzi-Falconi, Marco
• Format: Article
• Language: English
• Subjects: Animals; Cell cycle; Cell Cycle - physiology; Cell differentiation; Cell division; Cells, Cultured; Chromatin; Chromatin - metabolism; Chromosomes; Cilia; Cilia - metabolism; ciliopathy; Detachment; Dido3; Efficiency; H3T3; Haspin; HDAC6; HEK293 Cells; Histone deacetylase; Histone H3; Histones; Histones - metabolism; Homeostasis; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Phosphorylation; Phosphorylation - physiology; primary cilia; Protein kinase; Protein Serine-Threonine Kinases - metabolism; Proteins; Threonine - metabolism; Zebrafish
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22147753

Primary cilia are commonly found on most quiescent, terminally differentiated cells and play a major role in the regulation of the cell cycle, cell motility, sensing, and cell-cell communication. Alterations in ciliogenesis and cilia maintenance are causative of several human diseases, collectively known as ciliopathies. A key determinant of primary cilia is the histone deacetylase HDAC6, which regulates their length and resorption and whose distribution is regulated by the death inducer-obliterator 3 (Dido3). Here, we report that the atypical protein kinase Haspin is a key regulator of cilia dynamics. Cells defective in Haspin activity exhibit longer primary cilia and a strong delay in cilia resorption upon cell cycle reentry. We show that Haspin is active in quiescent cells, where it phosphorylates threonine 3 of histone H3, a known mitotic Haspin substrate. Forcing Dido3 detachment from the chromatin prevents Haspin inhibition from impacting cilia dynamics, suggesting that Haspin activity is required for the relocalization of Dido3-HDAC6 to the basal body. Exploiting the zebrafish model, we confirmed the physiological relevance of this mechanism. Our observations shed light on a novel player, Haspin, in the mechanisms that govern the determination of cilia length and the homeostasis of mature cilia.