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Interplay Between the Ubiquitin Proteasome System and Mitochondria for Protein Homeostasis

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Interplay Between the Ubiquitin Proteasome System and Mitochondria for Protein Homeostasis Curr. Issues Mol. Biol. (2020) 35: 35-58. Interplay between the Ubiquitin Proteasome System and Mitochondria for Protein Homeostasis Mafalda Escobar-Henriques1*, Selver Altin1 and Fabian den Brave2 1Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging- Associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. 2Department of Molecular Cell Biology, Max Planck Institute of Biochemistry, Martinsried, Germany. *Correspondence: [email protected] htps://doi.org/10.21775/cimb.035.035 Abstract Introduction Eukaryotic cells are subdivided into membrane- In order to fulfl their biological function, proteins bound compartments specialized in diferent must fold into their native three-dimensional cellular functions and requiring dedicated sets of structures and organelles need to function prop- proteins. Although cells developed compartment- erly. Te factors controlling protein homeostasis specifc mechanisms for protein quality control, processes are collectively termed the proteostasis chaperones and ubiquitin are generally required network (Klaips et al., 2018). In sum, cells must for maintaining cellular proteostasis. Proteotoxic ensure either proper protein folding or -if this fails- stress is signalled from one compartment into undertake efcient elimination of malfunctioning another to adjust the cellular stress response. proteins or damaged organelles. A prominent role Moreover, transport of misfolded proteins in proteostasis is ensured by ATP-dependent cellu- between diferent compartments can bufer local lar machineries dedicated to proper protein folding, defects in protein quality control. Mitochondria called chaperones (Hartl et al., 2011). In turn, the are special organelles in that they possess an own central proteolytic components of this network are expression, folding and proteolytic machinery, the ubiquitin proteasome system (UPS), a soluble of bacterial origin, which do not have ubiquitin. machinery, and the lysosomes, organelles that Nevertheless, the importance of extensive cross- enclose peptidases with a powerful and non-specifc talk between mitochondria and other subcellular lytic capacity (Bard et al., 2018). Consequently, the compartments is increasingly clear. Here, we will UPS is the main proteolytic pathway of the cell for present local quality control mechanisms and dis- cytosolic substrates, being the lysosomes generally cuss how cellular proteostasis is afected by the responsible for the clearance of membrane proteins, interplay between mitochondria and the ubiquitin entire organelles and large protein aggregates (Ker- proteasome system. scher et al., 2006; Amm et al., 2014). Both processes caister.com/cimb 35 Curr. Issues Mol. Biol. Vol. 35 194 | Escobar-Henriques et al. rely on the ear-marking of the desired protein with ubiquitin. In addition, autophagy requires the ubiq- uitin-like proteins or Atg8(yeast)/LC3(mammals). Organelles, despite being functional units with dedicated roles, must respond to their cellular environment. Mitochondria – the cellular energy powerhouse – are special semi-autonomous orga- nelles, which evolved through a symbiotic event of alpha-proteobacterium at the origin of a eukaryotic cell (Zimorski et al., 2014). Mitochondria possess an own DNA and the machineries allowing its replication, transcription and translation, originat- Figure 12.1 Crosstalk of cytosolic and mitochondrial ing from their bacterial ancestors, thus resembling proteostasis. Protein aggregates or malfunctional proteins activate diferent proteolytic pathways for the ones from free living prokaryotes (Falkenberg their clearance. Mitochondria as well as the cytosol et al., 2007; D’Souza and Minczuk, 2018). During harbour their own proteolytic machineries providing evolution of this endosymbiotic process, most of clearance of damaged proteins. Nevertheless, an the mitochondrial genetic information was trans- extensive interplay between mitochondria and their ferred to the nucleus. Tis means that most proteins environment is key to maintain cellular homeostasis. located at mitochondria need to be imported from the cytoplasm, rendering mitochondrial quality control processes fundamentally important for the cross-functional concepts. First, we focus on the biogenesis of this essential organelle (Pfanner et al., role of mitochondria in coping with excessive 2019). Terefore, the presence at mitochondria of cytosolic proteostasis. Tese fndings illustrate the specifc chaperones and proteases is not surpris- proteolytic power of mitochondria, which does ing. As mentioned, these are closely homologous not depend on ubiquitin. Second, we describe sev- to their bacterial relatives and make up for local eral cytosolic and ubiquitin-dependent pathways protein quality control (Voos et al., 2016). Perhaps engaging on mitochondria. We present integrated for this reason, it was long assumed that mito- cellular responses, requiring ubiquitin and the chondrial proteostasis was ubiquitin-independent. proteasome or the autophagic marker LC3 and Instead, it is now clear that mitochondrial stress is lysosomes, which contribute to alleviate mitochon- also engaging cytosolic and lysosomal proteostasis drial stress. Finally, we present the dual role of the networks, including ubiquitin and the UPS but also peptidyl-tRNA hydrolase Vms1 (yeast)/ANKZF1 Atg8/LC3 and the lysosomes (Germain, 2008; (mammals) in ribosomal quality control and Escobar-Henriques and Langer, 2014; Topf et al., mitochondrial proteostasis, being both processes 2016; Braun and Westermann, 2017; D’Amico et regulated by ubiquitin. al., 2017). Te most prominent example is certainly the mitophagy process, where damaged mitochon- dria are selectively degraded (McWilliams and Principles of protein quality Muqit, 2017). Reciprocally, mitochondria also control – cytosolic and sense and regulate external stress, clearly impacting mitochondrial on cellular homeostasis and longevity and certainly Aberrant folding or unfolding does not only relevant for neurodegeneration (Chung et al., 2018; compromise the afected protein but is also Guaragnella et al., 2018; Ruan et al., 2018). accompanied with a great risk of disrupting the In this review, we describe novel insights on functionality of other proteins, by undergoing non- how mitochondria crosstalk and bi-directionally specifc protein–protein interactions. Especially cooperate with their cellular environment to deal metastable proteins with disordered regions (up with proteotoxic stress (see Fig. 12.1). Afer a to 30% of the mammalian proteome) are prone general overview on quality control – cytosolic to undergo unwanted interactions and form toxic and mitochondrial – we then describe emerging protein aggregates, which are associated with caister.com/cimb 36 Curr. Issues Mol. Biol. Vol. 35 Mitochondria and Ubiquitin in Proteostasis | 195 neurodegenerative diseases (Dunker et al., 2008). proteins, thereby preventing non-specifc interac- Tis underlines the broad importance of proteome tions, until proteins reach their native state and/or surveillance. In addition, the vast majority of fnal destination. proteins are synthesized by cytosolic ribosomes, Te intrinsic activity of Hsp70 alone is low and followed by post- or co-translational transport of therefore folding requires the help of additional proteins to their fnal destination (Dudek et al., factors. On the one hand, efcient Hsp70 func- 2013). Tus, the cytosolic quality control machin- tion requires one of several structurally unrelated eries are essential for the integrity of the entire nucleotide exchange factors (NEFs), which pro- cellular proteome. mote the exchange between ADP and ATP. On the other hand, ATPase activity is stimulated by Hsp40 Quality control components in the chaperones, also called J-proteins, which bind the cytoplasm substrates and deliver them to Hsp70, thus avoiding their aggregation. Terefore, substrate specifcity of Protein folding Hsp70 is mainly determined by Hsp40 chaperones Chaperones are central players in protein quality (Kampinga and Craig, 2010). Tese ofen contain control, which support other proteins in acquir- substrate-binding domains themselves and medi- ing their functional conformation, without usually ate the transfer of substrates to Hsp70, depending being present in the fnal structure (Hartl, 1996). on their J-domain. In addition, several specialized Unfolded proteins expose hydrophobic residues, Hsp40s lack a substrate-binding domain but local- normally buried inside their three-dimensional ize Hsp70 within the cell to the vicinity of certain structure, being such non-native regions recog- substrates. For instance, the Hsp40 Zuo1 targets nized by chaperones. Chaperones promote folding cytosolic Hsp70 to the ribosomal exit tunnel to by ATP dependent cycles of binding and release of aid in folding of nascent proteins (Yan et al., 1998; their substrate proteins, till they reach their native Gautschi et al., 2001). In sum, Hsp40 chaperones, state. Tus, by assisting in protein folding, chaper- in conjunction with NEFs, are responsible for the ones prevent unspecifc interactions and protein versatile functions exerted by the Hsp70 system aggregation and refold stress-denatured proteins. (Fig. 12.2). However, if encountering terminally misfolded pro- teins, chaperones also cooperate with proteolytic Protein ubiquitination and turnover by machineries in their degradation (Tyedmers et al., the UPS 2010; Balchin et al., 2016). When proteins
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