Protein Kinase A-Mediated Septin7 Phosphorylation Disrupts Septin Filaments and Ciliogenesis

Abstract

Septins are GTP-binding proteins that form heteromeric filaments for proper cell growth and migration. Among the septins, septin7 (SEPT7) is an important component of all septin filaments. Here we show that protein kinase A (PKA) phosphorylates SEPT7 at Thr197, thus disrupting septin filament dynamics and ciliogenesis. The Thr197 residue of SEPT7, a PKA phosphorylating site, was conserved among different species. Treatment with cAMP or overexpression of PKA catalytic subunit (PKACA2) induced SEPT7 phosphorylation, followed by disruption of septin filament formation. Constitutive phosphorylation of SEPT7 at Thr197 reduced SEPT7‒SEPT7 interaction, but did not affect SEPT7‒SEPT6‒SEPT2 or SEPT4 interaction. Moreover, we noted that SEPT7 interacted with PKACA2 via its GTP-binding domain. Furthermore, PKA-mediated SEPT7 phosphorylation disrupted primary cilia formation. Thus, our data uncover the novel biological function of SEPT7 phosphorylation in septin filament polymerization and primary cilia formation.

UBC Mediated by SEPT6 Inhibited the Progression of Prostate Cancer

“…Our study found that SEPT6 inhibited the ubiquitin-coding gene UBC expression, affected the expression level of downstream cell proliferation-related genes, and thus affected the malignant of prostate cancer. Posttranslational modification plays an important role in regulating the Septin-septin interaction and controlling the formation of high-order septin complexes, and such modifications include SUMOylation, acetylation, ubiquitination, and phosphorylation [30]. The covalence modification of proteins by ubiquitination is the main regulatory mechanism of protein degradation and quality control, endocytosis, vesicle transport, cell cycle control, stress response, DNA repair, growth factor signal transduction, transcription, gene silencing, and other biological fields [31].…”

Phosphoregulation of the septin cytoskeleton in neuronal development and disease

“…Mitogen‐activated protein kinase‐activated protein kinase 5 (MAPKAPK5 or MK5) of the MAPKAPK family is an in vivo Septin 8 interactor with in vitro phosphorylation sites at Ser242 and Ser271 in the more C‐terminal region of Septin 8's GTP‐binding domain (Shiryaev, 2012). cAMP‐dependent protein kinase (PKA) of the PKA family phosphorylates human Septin 7 at Thr197 in vivo (Wang et al, 2021). This site is highly conserved in mammals, and the PKA target motif resides in human Septins 2, 3, 4, 9, 10, 11, 12, and 14 (Wang et al, 2021).…”

“…cAMP‐dependent protein kinase (PKA) of the PKA family phosphorylates human Septin 7 at Thr197 in vivo (Wang et al, 2021). This site is highly conserved in mammals, and the PKA target motif resides in human Septins 2, 3, 4, 9, 10, 11, 12, and 14 (Wang et al, 2021). This motif on Septin 12 contains an in vivo PKA phosphorylation site at Ser198 (Shen et al, 2017).…”

“…While trends in mammalian septin phosphorylation are convoluted, trends across species are evident, including the conservation of several phosphorylation sites described above (Shiryaev, 2012; Wang et al, 2021; Yadav et al, 2017). Fungal septin phosphorylation is well‐documented, and fungal septins similarly interact with protein kinases of the cyclin‐dependent, Ste20, and calcium/calmodulin‐regulated kinase‐like (CAMKL) kinase families (reviewed in Hernández‐Rodríguez & Momany, 2012).…”

“…Septin 9 is similarly N‐terminally phosphorylated by GSK3B, but further investigation is necessary to determine if this GSK3B‐mediated modification regulates Septin 9 in the same manner (Shinde et al, 2017). PKA‐mediated phosphorylation of Septin 7 in its GTP‐binding domain reduces Septin 7 protein expression and self‐interaction (Wang et al, 2021). This leads to disruption of septin filament formation and ciliogenesis deficits (Wang et al, 2021).…”