Synaptic localization of the SUMOylation‐regulating protease SENP5 in the adult mouse brain

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The post‐translational modification of proteins through the addition of small ubiquitin‐like modifier (SUMO) proteins regulates a broad range of cellular functions including mitosis, cell differentiation, and synaptic transmission (Deyrieux & Wilson, 2017; Gwizdek, Casse, & Martin, 2013; Henley, Craig, & Wilkinson, 2014; Mukhopadhyay & Dasso, 2017). SUMOs have thus been implicated in several disease states such as cancer, diabetes, cardiovascular disease, and neurological disorders (Abe et al., 2017; Eifler & Vertegaal, 2015; Henley et al., 2014; Lee, Choi, & Baek, 2017; Zhang, Chen, Zhou, Yang, & Wang, 2017). SUMOs are covalently attached to target proteins by conjugating enzymes in a process called SUMOylation. In vertebrates, there are four SUMO proteins: SUMO1–4. SUMO2 and SUMO3 share a 96% sequence identity and are thus often referred to collectively as SUMO2/3. SUMOylation by SUMO2/3 but not SUMO1 yields a product that is covalently modified with the polySUMO chain. SUMOs are processed by proteases in order to expose a C‐terminal diglycine motif that is essential for conjugation to the lysine residue of the target protein. Because of a unique proline residue located at position 90, the diglycine motif of SUMO4 cannot be exposed and thus cannot be rendered into a mature conjugatable form (Owerbach, McKay, Yeh, Gabbay, & Bohren, 2005).
Conjugated SUMOs are removed from substrate proteins by sentrin/SUMO‐specific proteases (SENPs). There are six SENPs in mammals: SENP1–3 and SENP5–7. Of these, SENP1, 2, and 5 have endopeptidase activity, which is required for the generation of mature SUMOs, in addition to isopeptidase activity, which is necessary for SUMO deconjugation (Hickey, Wilson, & Hochstrasser, 2012; Nayak & Muller, 2014). Thus, SENPs are important for both SUMOylation and deSUMOylation. Of note, SUMO deconjugation by SENPs is partially SUMO paralogue‐specific. For example, SENP3 and 5 have a preference for SUMO2/3 compared to SUMO1 (Hickey et al., 2012).
Increasing evidence highlights the physiological and pathological roles of SUMOylation in the nervous system (Henley et al., 2014; Krumova & Weishaupt, 2013). Synaptic vesicle exocytosis is regulated by SUMOylation of the active zone protein Rab3‐interacting molecule 1α (RIM1α) (Girach, Craig, Rocca, & Henley, 2013). SUMOylation has also been implicated in long‐term synaptic plasticity, specifically the regulation of the number of postsynaptic surface receptors. Inhibiting SUMOylation prevents AMPA receptor surface expression likely by facilitating Arc‐mediated AMPA receptor internalization (Jaafari et al., 2013; Rial Verde, Lee‐Osbourne, Worley, Malinow, & Cline, 2006; Shepherd et al., 2006). In contrast, SUMOylation of the kainate receptor subunit GluK2 leads to receptor internalization (Jaafari et al., 2013; Martin, Nishimune, Mellor, & Henley, 2007). Several proteins that are causatively associated with neurological disorders including amyloid precursor protein (APP), tau, and huntingtin are subject to SUMOylation (Dorval & Fraser, 2006; Steffan et al., 2004; Takahashi, Ishida, Komano, & Takahashi, 2008; Zhang & Sarge, 2008), implicating SUMOylation in the pathogenesis of Alzheimer's disease (AD) and Huntington's disease (HD). Additionally, SUMOylation has been shown to regulate the balance of fission and fusion in mitochondria (Harder, Zunino, & McBride, 2004; Peng, Ren, Yang, & Luo, 2016; Zunino, Schauss, Rippstein, Andrade‐Navarro, & McBride, 2007). Taken together, it can be posited that SUMOylation plays a role in the pathogenesis of neurological disorders caused by imbalances in mitochondrial dynamics such as Parkinson's disease (PD), AD, and HD.
We recently demonstrated that SUMOs and the conjugating enzyme Ubc9 are widely expressed in many brain regions (Hasegawa, Yoshida, Nakamura, & Sakakibara, 2014), consistent with the ubiquitous roles of SUMOylation in the brain. To advance the current understanding of the functional roles of SUMOylation in the nervous system, it is important to elucidate the distribution of not only SUMO conjugating components but also the molecules mediating deconjugation.
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