Abstract
Septins are critical for numerous cellular processes through the formation of heteromeric filaments and rings indicating the importance of structural regulators in septin assembly. Several posttranslational modifications (PTMs) mediate the dynamics of septin filaments in yeast. However, little is known about the role of PTMs in regulating mammalian septin assembly, and the in vivo significance of PTMs on mammalian septin assembly and function remains unknown. Here, we showed that SEPT12 was phosphorylated on Ser198 using mass spectrometry, and we generated SEPT12 phosphomimetic knock-in (KI) mice to study its biological significance. The homozygous KI mice displayed poor male fertility due to deformed sperm with defective motility and loss of annulus, a septin-based ring structure. Immunohistochemistry of KI testicular sections suggested that SEPT12 phosphorylation inhibits septin ring assembly during annulus biogenesis. We also observed that SEPT12 was phosphorylated via PKA, and its phosphorylation interfered with SEPT12 polymerization into complexes and filaments. Collectively, our data indicate that SEPT12 phosphorylation inhibits SEPT12 filament formation, leading to loss of the sperm annulus/septin ring and poor male fertility. Thus, we provide the first in vivo genetic evidence characterizing importance of septin phosphorylation in the assembly, cellular function and physiological significance of septins.
Highlights
Septins are highly conserved GTP-binding proteins in eukaryotes that polymerize into heteromers and further higher-order structures, such as filaments, rings and gauzes
Septin polymerization into filaments and rings are built for numerous cellular processes, and misregulation of septin filaments is implicated in several human diseases
The Saccharomyces cerevisiae septins are sumoylated during the cell cycle, and mutation of sumoylation sites interferes with the disassembly of the septin ring at a previous site of division [10]
Summary
Septins are highly conserved GTP-binding proteins in eukaryotes that polymerize into heteromers and further higher-order structures, such as filaments, rings and gauzes. These structures are required for a wide range of cellular processes, including cell cycle regulation, cytokinesis, spermiogenesis, ciliogenesis and neurogenesis [1,2,3,4,5,6,7]. Posttranslational modifications (PTMs) of yeast septins, such as sumoylation, phosphorylation and acetylation, modulate the dynamics of septin filament formation during the yeast cell cycle [9]. Different phosphomimetic mutations in yeast Shs lead to no filament formation or distinct organizations of higher-order structures, such as rings and gauzelike structures [12]. The mechanism underlying the contribution of PTMs to the dynamics of higher-order structures remains unknown
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