DYRK3 phosphorylates SNAPIN to regulate axonal retrograde transport and neurotransmitter release

Abstract

Among the five members of the dual-specificity tyrosine-phosphorylation-regulated kinase (DYRK) family, the cellular functions of DYRK3 have not been fully elucidated. Some studies have indicated limited physiological roles and substrates of DYRK3, including promotion of glioblastoma, requirement in influenza virus replication, and coupling of stress granule condensation with mammalian target of rapamycin complex 1 signaling. Here, we demonstrate that serum deprivation causes a decrease in intracellular DYRK3 levels via the proteolytic autophagy pathway, as well as the suppression of DYRK3 gene expression. To further demonstrate how DYRK3 affects cell viability, especially in neurons, we used a yeast two-hybrid assay and identified multiple DYRK3-binding proteins, including SNAPIN, a SNARE-associated protein implicated in synaptic transmission. We also found that DYRK3 directly phosphorylates SNAPIN at the threonine (Thr) 14 residue, increasing the interaction of SNAPIN with other proteins such as dynein and synaptotagmin-1. In central nervous system neurons, SNAPIN is associated with and mediate the retrograde axonal transport of diverse cellular products from the distal axon terminal to the soma and the synaptic release of neurotransmitters, respectively. Moreover, phosphorylation of SNAPIN at Thr-14 was found to positively modulate mitochondrial retrograde transport in mouse cortical neurons and the recycling pool size of synaptic vesicles, contributing to neuronal viability. In conclusion, the present study demonstrates that DYRK3 phosphorylates SNAPIN, positively regulating the dynein-mediated retrograde transport of mitochondria and SNARE complex-mediated exocytosis of synaptic vesicles within the neurons. This finding further suggests that DYRK3 affects cell viability and provides a novel neuroprotective mechanism.

Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 3 Expression and Its Correlation with Prognosis and Growth of Serous Ovarian Cancer: Correlation of DYRK3 with Ovarian Cancer Survival

“…The retrospective analysis of a sizable SOC cohort revealed that elevated DYRK3 expression is independently associated with adverse overall survival outcomes. Our findings align with emerging research suggesting DYRK3 as a crucial player in cancer biology [ 9 ]. While DYRK3 has been implicated in various malignancies, its specific role in ovarian cancer remained largely unexplored.…”

Exploring Retrograde Trafficking: Mechanisms and Consequences in Cancer and Disease

“…Links between impaired autophagy and disease are evident in neurodegenerative diseases. RT is essential for the trafficking of autophagic vacuoles from distal locations in neurons to the soma, where most lysosomes reside for autophagic clearance [124,132]. Disrupted RT was shown by Tammineni et al to promote autophagic stress in the context of AD [124].…”