Bassoon and piccolo regulate ubiquitination and link presynaptic molecular dynamics with activity‐regulated gene expression

Abstract

Release of neurotransmitter is executed by complex multiprotein machinery, which is assembled around the presynaptic cytomatrix at the active zone. One well-established function of this proteinaceous scaffold is the spatial organization of synaptic vesicle cluster, the protein complexes that execute membrane fusion and compensatory endocytosis, and the transmembrane molecules important for alignment of pre- and postsynaptic structures. The presynaptic cytomatrix proteins function also in processes other than the formation of a static frame for assembly of the release apparatus and synaptic vesicle cycling. They actively contribute to the regulation of multiple steps in this process and are themselves an important subject of regulation during neuronal plasticity. We are only beginning to understand the mechanisms and signalling pathways controlling these regulations. They are mainly dependent on posttranslational modifications, including phosphorylation and small-molecules conjugation, such as ubiquitination. Ubiquitination of presynaptic proteins might lead to their degradation by proteasomes, but evidence is growing that this modification also affects their function independently of their degradation. Signalling from presynapse to nucleus, which works on a much slower time scale and more globally, emerged as an important mechanism for persistent usage-dependent and homeostatic neuronal plasticity. Recently, two new functions for the largest presynaptic scaffolding proteins bassoon and piccolo emerged. They were implied (1) in the regulation of specific protein ubiquitination and proteasome-mediated proteolysis that potentially contributes to short-term plasticity at the presynapse and (2) in the coupling of activity-induced molecular rearrangements at the presynapse with reprogramming of expression of neuronal activity-regulated genes.

A Multiple Piccolino-RIBEYE Interaction Supports Plate-Shaped Synaptic Ribbons in Retinal Neurons

“…One of the highly conserved AZ components is the large (Ͼ500 kDa) scaffold protein Piccolo, which organizes various aspects of presynaptic function at chemical synapses (Cases-Langhoff et al, 1996;Wang et al, 1999;Gundelfinger et al, 2016). Among these are functions in AZ assembly during synaptogenesis (Shapira et al, 2003), the dynamic regulation of presynaptic actin (Waites et al, 2011;Wagh et al, 2015), the control of presynaptic proteostasis (Waites et al, 2013;Ivanova et al, 2016), the regulation of activity-dependent communication between the presynapse and the nucleus (Ivanova et al, 2015), and the organization of the readily releasable pool of SVs (Butola et al, 2017;Parthier et al, 2018). Piccolo possesses regions of high sequence similarity to Bassoon, another conserved AZ protein.…”

Cullin-associated NEDD8-dissociated protein 1, a novel interactor of rabphilin-3A, deubiquitylates rabphilin-3A and regulates arginine vasopressin secretion in PC12 cells

“…The ubiquitin-proteasome system (UPS) modulates the levels of synaptic proteins, such as synaptophysin, syntaxin, Munc1 and Rab3-interacting molecule 1 (RIM1), and Bassoon and Piccolo in the presynaptic active zone [28][29][30][31][32][33]. Yao et al reported that SCRAPPER, an E3 ubiquitin ligase, directly binds to and ubiquitylates RIM1 regulating synaptic vesicle release via RIM1 degradation and proteasome activity in vivo [32].…”

CB1receptor-mediated inhibitory LTD triggers presynaptic remodeling via protein synthesis and ubiquitination

“…398relies on ubiquitination. The regulation of presynaptic ubiquitination is likely achieved through the 399 targeted expression of different E2 and E3 ubiquitin ligases(Hallengren et al, 2013) or via 400 presynaptic cytomatrix proteins themselves(Ivanova et al, 2016; Waites et al, 2013). This raises 401 the yet unexplored possibility that presynaptic structural dynamics and UPS activity are tightly 402linked.…”