Abstract
Protein modification by Small Ubiquitin-like MOdifier (SUMO) entities is involved in a number of neuronal functions, including synaptogenesis and synaptic plasticity. Tomosyn-1 (syntaxin-binding protein 5; STXPB5) binds to t-SNARE (Soluble NSF Attachment Protein Receptor) proteins to regulate neurotransmission and is one of the few neuronal SUMO substrate proteins identified. Here we used yeast two-hybrid screening to show that tomosyn-1 interacts with the SUMO E3 ligase PIASγ (Protein Inhibitor of Activated STAT; PIAS4 or ZMIZ6). This novel interaction involved the C-terminus of tomosyn-1 and the N-terminus of PIASγ. It was confirmed by two-way immunoprecipitation experiments using the full-length proteins expressed in HEK293T cells. Tomosyn-1 was preferentially modified by the SUMO-2/3 isoform. PIASγ-dependent modification of tomosyn-1 with SUMO-2/3 presents a novel mechanism to adapt secretory strength to the dynamic synaptic environment.
Highlights
SUMOylation involves covalent attachment of a 12 kDa Small Ubiquitin-related MOdifier (SUMO) protein to a protein substrate
In this study we report that SUMO-2/3 modification of tomosyn-1 is mediated by its interaction with the SUMO E3 ligase PIASc, identifying a novel signaling pathway of potential importance for the regulation of synaptic transmission
Interacts with the SUMO E3 ligase PIASc In order to find novel protein interactors, C-terminal fragments of tomosyn-1 were used as bait in a yeast two-hybrid experiment
Summary
SUMOylation involves covalent attachment of a 12 kDa Small Ubiquitin-related MOdifier (SUMO) protein to a protein substrate. The mechanisms behind SUMO-isoform selectivity remain elusive, as well as their functional differences [1]. SUMOylation modulates spine development, spine structure and function as well as synaptogenesis and synaptic plasticity [9]. The latter could be mediated by activity-dependent redistribution of the SUMOylation machinery [10]. SUMO-2/3 attachment is increased during ischemic stress in neurons, which could serve as a neuroprotective mechanism [11,12,13,14,15]. Only a few neuronal SUMO substrates have been identified (Reviewed in [17])
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