Tubulin glycylation controls axonemal dynein activity, flagellar beat, and male fertility

Abstract

Posttranslational modifications of the microtubule cytoskeleton have emerged as key regulators of cellular functions, and their perturbations have been linked to a growing number of human pathologies. Tubulin glycylation modifies microtubules specifically in cilia and flagella, but its functional and mechanistic roles remain unclear. In this study, we generated a mouse model entirely lacking tubulin glycylation. Male mice were subfertile owing to aberrant beat patterns of their sperm flagella, which impeded the straight swimming of sperm cells. Using cryo–electron tomography, we showed that lack of glycylation caused abnormal conformations of the dynein arms within sperm axonemes, providing the structural basis for the observed dysfunction. Our findings reveal the importance of microtubule glycylation for controlled flagellar beating, directional sperm swimming, and male fertility.

Epidemiological overview of multidimensional chromosomal and genome toxicity of cannabis exposure in congenital anomalies and cancer development

“…Cannabinoids have long been recognized to reduce the synthesis of major macromolecules of life including DNA, RNA proteins and histones 13 , 18 , 60 , 99 – 104 . Reduction in the linker histone H1 has recently been shown to comprise a major oncogenic mechanism by making genes more accessible for transcription 105 . One of the proteins whose synthesis is impeded is tubulin 4 , 16 .…”

“…Deranged microtubular function has been linked with chromosomes sliding off the mitotic spindle in anaphase and the formation of micronuclei 4 , 6 , 7 , 107 which are described as being a major generator of the genetic chaos of cancer 4 , 107 – 118 . Indeed, just as histones undergo post-translational modifications tubulin has also been shown to undergo post-translational modifications which target the tubulin monomers for different subcellular destinations 105 . Errors in this “tubulin code” have been linked to disorders of flagellar function so that sperm are not able to swim normally in a linear trajectory and go round in circles and fail to correctly target oocytes which is believed to be a potentially significant cause of male infertility 105 .…”

“…Indeed, just as histones undergo post-translational modifications tubulin has also been shown to undergo post-translational modifications which target the tubulin monomers for different subcellular destinations 105 . Errors in this “tubulin code” have been linked to disorders of flagellar function so that sperm are not able to swim normally in a linear trajectory and go round in circles and fail to correctly target oocytes which is believed to be a potentially significant cause of male infertility 105 . Hence whilst for descriptive purposes it is useful to describe cannabinoid-related molecular aberrations in various stratified layers and subcellular compartments, it seems likely that in reality the various layers are intimately crosslinked and molecularly interdependent 53 , 54 , 119 – 121 .…”

Epigenetically Mediated Ciliogenesis and Cell Cycle Regulation, and Their Translational Potential

“…The role of tubulin glycylation in the regulation of primary cilia biogenesis has been reported recently, which has been confirmed by the depletion of glycylation-catalyzing enzymes [ 74 ]. There are three TTLLs involved in tubulin glycylation in mammals: two enzymes—TTLL3 and TTLL8—function as the initiating glycylases to add the first glycine residues to tubulin, whereas TTLL10 contributes to the elongation of glycine chains and the formation of polyglycylation [ 75 ]. However, the mechanism of epigenetic regulation on TTLLs and CCP is as yet unclear.…”

Comparative Proteomics and Phosphoproteomics Analysis Reveal the Possible Breed Difference in Yorkshire and Duroc Boar Spermatozoa

“…Mature mammalian sperm are highly differentiated haploid cells which almost silenced at the level of transcriptional and translational regulation. As the carrier of patrilineal genes, sperm cells are unique in elongated structure and function and are tightly regulated by the existing proteins and the posttranslational modifications (PTM), which have served as a resource pool for screening of key targets involved in sperm motility regulation (Samanta et al, 2016;Dai et al, 2019b;Gadadhar et al, 2021). Owing to this essential role in sperm cells, the study of sperm protein is of great significance for clarifying the physiological process of mammalian spermatogenesis and conception.…”