The SUMO arena goes mitochondrial with MAPL.

摘要: Mitochondria are versatile organelles that provide most of the ATP required for cellular endoergonic processes, coordinate biosynthesis several metabolites, and shape amplify Ca2+ signalling apoptosis (Dimmer & Scorrano, 2006). These multifaceted tasks mirrored by their complex morphology ultrastructure (Frey Mannella, 2000), which affect processes as diverse apoptosis, signalling, formation dendritic spines chemotaxis. The tight regulation mitochondrial is crucial importance homeostasis, exemplified fact mutations in core mitochondria-shaping proteins associated with neurodegenerative diseases 2006). Mitochondrial determined a dynamic equilibrium between fission fusion. In mammalian cells, fusion controlled outer membrane mitofusin 1 2, inner protein optic atrophy Dynamin-related (DRP1) an evolutionarily conserved large dynamin-like GTPase participates multistep process fission. DRP1 recruited to undergoes self-assembly into ring-like oligomeric structure wraps around prospective site fragment organelle (van der Bliek, 2000). precise mechanisms regulate this remain elusive. Cellular cues, including cyclic AMP signals, can lead change inducing post-translational modification DRP1, thereby influencing its localization activity (Jahani-Asl Slack, 2007; Cereghetti et al, 2008). After translocation mitochondria, levels counterbalancing ubiquitination SUMOylation. issue EMBO reports, Braschi colleagues (2009) report identification small ubiquitin-like modifier (SUMO) E3 ligase mediates SUMOylation and, therefore, regulates fission. Ubiquitination important regulates, among other things, degradation. It catalysed three-step reaction involves ubiquitin-activating (E1), ubiquitin-conjugating (E2) ubiquitin-ligating (E3) enzymes. Polyubiquitinated usually degraded 26S proteasome complex, whereas types ubiquitination—such mono-ubiquitination—can be involved proteasomal-independent or lysosomal degradation (Hershko Ciechanover, 1998). Notably, turnover not only cytoplasmic, soluble proteins, but also substrates integral components endoplasmic reticulum (Werner 1996). Furthermore, stability localized different subcompartments influenced proteasomal inhibition, suggesting role (Neutzner Indeed, earlier studies reported existence E1 E2 enzymes within mitochondria (Magnani 1991; Schwartz 1992). addition, more recent growing body evidence shows contain specific ligases prominent dynamics. particular, Mitol/March5—a ubiquitin embedded membrane—participates (FIS1; Yonashiro 2006), 2 (Nakamura stabilized when catalytic domain Mitol/March5 mutated (Karbowski 2007), highlighting morphology. SUMO conjugated targets. Similar ubiquitination, performed three enzymes—known SUMO E1, E3, analogy ubiquitination—and it readily reversed proteases. Two classes have recently been identified: first has essential RING-like similarities RING finger ligases, second no obvious similarity ligases. specificity conjugation proteolysis seems achieved confining proteases restricted subcellular compartments. wide range from cell-cycle control transcriptional regulation, signal transduction (Verger 2003). The hint were strangers was put forward five years ago McBride group. founding paper, they showed pro-fission interacts SUMO1—which concentrated at sites fission—and high SUMO1 stabilize promote fragmentation (Harder 2004). This finding unveiled additional layer However, keystone missing construction: SUMOylates mitochondria. group now reports ligase, closing circle (Braschi 2009). They had previously shown membrane-anchored contains domain. Being true Canadians, christened MAPL, mitochondrial-anchored (Neuspiel 2008)! domain, MAPL could either ligase. Now, using synthetic peptides containing consensus sequence well purified organelles, show RING-finger activity, although, presence concentrations ubiquitinating enzymes, subject auto-ubiquitination. Nonetheless, downregulation leads reduction conjugates without significantly affecting status indicating predominant physiological MAPL. authors able reconstituted vitro assays, emphasizing involvement maintenance morphology. accordance previous results overexpression enhances RING-domain-dependent manner de-SUMOylated protease SUMO1/sentrin-specific peptidase 5 (SENP5), resulting decreased (Zunino 2007). MAPL silencing reduced changing morphology, suggests although positively fission, might obligatory process. Alternatively, effect on counterbalanced if stabilizes such mitofusins. just remote possibility, found rate after knockdown. definition interorganellar cross-talk, which, case juxtaposition reticulum, crucially (de Brito selectively included mitochondria-derived vesicles bud transported peroxisomes. An open unexplored whether peroxisomes final destination SUMOylated would enclosed vesicles. How does recognize DRP1? principle, depend proximity—that is, pool DRP1. As driven dephosphorylation Ser 637 (Cereghetti 2008), tempting speculate cooperate determine amount active requires phosphorylated residue immediately downstream sequence, rather than dephosphorylation. Interestingly, kinase A (PKA), anchored (Affaitati 2003). regulatory network therefore envisioned occurs retain rephosphorylated PKA. scenario introduces possibility dynamics multiple events emanate cytoplasm converge (Fig 1). Figure 1 The trafficking enlarged boxed area. putative regulating accumulation assembly shown, calcineurin-mediated ... In identified MAPL-induced SUMOylation, opens exciting and/or function, stabilization coordination organelle. coming years, we will undoubtedly learn present how controls physiology pathology