SUMOylation controls the neurodevelopmental function of the transcription factor Zbtb20

Abstract

SUMOylation is a dynamic post‐translational protein modification that primarily takes place in cell nuclei, where it plays a key role in multiple DNA‐related processes. In neurons, the SUMOylation‐dependent control of a subset of neuronal transcription factors is known to regulate various aspects of nerve cell differentiation, development, and function. In an unbiased screen for endogenous SUMOylation targets in the developing mouse brain, based on a His6‐HA‐SUMO1 knock‐in mouse line, we previously identified the transcription factor Zinc finger and BTB domain‐containing 20 (Zbtb20) as a new SUMO1‐conjugate. We show here that the three key SUMO paralogues SUMO1, SUMO2, and SUMO3 can all be conjugated to Zbtb20 in vitro in HEK293FT cells, and we confirm the SUMOylation of Zbtb20 in vivo in mouse brain. Using primary hippocampal neurons from wild‐type and Zbtb20 knock‐out (KO) mice as a model system, we then demonstrate that the expression of Zbtb20 is required for proper nerve cell development and neurite growth and branching. Furthermore, we show that the SUMOylation of Zbtb20 is essential for its function in this context, and provide evidence indicating that SUMOylation affects the Zbtb20‐dependent transcriptional profile of neurons. Our data highlight the role of SUMOylation in the regulation of neuronal transcription factors that determine nerve cell development, and they demonstrate that key functions of the transcription factor Zbtb20 in neuronal development and neurite growth are under obligatory SUMOylation control.

Postnatal age-differential ASD-like transcriptomic, synaptic, and behavioral deficits in Myt1l-mutant mice

“…Functionally, Slc1a2 in astrocytes transports glutamate and aspartate for their removal from the synaptic cleft, and Slc7a11 exchanges glutamate with cysteine in astrocytes (Alcoreza et al, 2021), regulating ambient glutamate concentration and synaptic transmission. Zbtb20 regulates neuronal development, synaptic transmission and plasticity, memory, and emotion (Jones et al, 2018;Ripamonti et al, 2020). Itpr2 regulates somatic calcium signaling and adenosine triphosphate (ATP) release in astrocytes and astrocyte-dependent synapse elimination (Yang et al, 2016) and microglial calcium signaling and differentiation (Mei et al, 2021).…”

Characterizing the differential distribution and targets of Sumo paralogs in the mouse brain

“…Increasing evidence indicates that SUMOylation plays roles in the brain, e.g. in neuronal development or learning and memory(Ripamonti et al, 2020). Furthermore, SUMOylation has been linked with various brain disorders, including Autism Spectrum Disorder, Epilepsy, Schizophrenia, and neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis (Bernstock et al, 2018; Krumova and Weishaupt, 2013; Osmanovic et al, 2022; Rousseaux et al, 2016).…”

“…Sumo2 is the only essential Sumo paralog, and has key roles in neurodevelopment, nerve cell function, and neurological diseases(Krumova and Weishaupt, 2013; Ripamonti et al, 2020; Stankova et al, 2018; Wang et al, 2014b). To uncover some of the unique clientele targeted by Sumo2, we performed HA tag immunoprecipitation paired with mass spectrometry.…”

Small ubiquitin‐like modifier 2 (SUMO2) is critical for memory processes in mice

“…For example, protein phosphorylation plays an essential role in many aspects of synaptic plasticity by modifying key proteins including α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors 1 . Accumulating evidence suggests that small ubiquitin‐like modifier (SUMO) conjugation (SUMOylation), an evolutionarily conserved posttranslational modification, regulates a wide range of neuronal function, and is involved in learning and memory processes as well as neurogenerative diseases 2‐11 …”

“…1 Accumulating evidence suggests that small ubiquitin-like modifier (SUMO) conjugation (SUMOylation), an evolutionarily conserved posttranslational modification, regulates a wide range of neuronal function, and is involved in learning and memory processes as well as neurogenerative diseases. [2][3][4][5][6][7][8][9][10][11] SUMOylation can affect the stability, activity, and localization of target proteins, and modulate their interactions with other proteins. 3 Three SUMOs-SUMO1, SUMO2, and SUMO3-are widely expressed in mammalian cells.…”