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Home , SUMO2, SUMO4, Ubiquitin

Curr. Issues Mol. Biol. (2020) 35: 99-108.

Role of and SUMO in Intracellular Trafcking

Maria Sundvall1,2,3*

1Institute of Biomedicine, University of Turku, Turku, Finland. 2Western Centre FICAN West, Turku University Hospital, Turku, Finland. 3Department of Oncology and Radiotherapy, University of Turku, Turku, Finland. *Correspondence: [email protected] htps://doi.org/10.21775/cimb.035.099

Abstract behaviour. In addition to e.g. chemical groups, Precise location of at a given time within such as phosphate groups, proteins can be modi- a is essential to convey specifc signals and fed by small polypeptides, such as ubiquitin and result in a relevant functional outcome. Small SUMO. Ubiquitin and SUMO share a similar ubiquitin-like modifcations, such as ubiquitin three-dimensional structure and are principally and SUMO, represent a delicate and diverse way covalently linked at (K) residues of sub- to transiently regulate intracellular trafcking strate proteins by a similar conjugation pathway events of existing proteins in cells. Trafcking (Hershko et al., 1998; Hay, 2013). Unlike ubiq- of multiple proteins is controlled reversibly by uitin, SUMO is preferentially atached at SUMO ubiquitin and/or SUMO directly or indirectly via consensus sites ΨKxE in substrates Ψ = hydropho- regulation of transport machinery components. bic residue with high preference for I or V, x = any Regulation is dynamic and multilayered, involv- ) under steady state conditions, but ing active crosstalk and interdependence between under stress conditions in particular more non- post-translational modifcations. However, in consensus sites are SUMOylated (Hendriks et al., most cases regulation appears very complex, and 2016). Mammals express ubiquitously SUMO1, the mechanistic details regarding how ubiquitin SUMO2 and SUMO3, whereas SUMO4 and and SUMO control location in cells are SUMO5 are only expressed in some tissues and not yet fully understood. Moreover, most of the their functional role is unclear (Pichler et al., fndings still lack in vivo evidence in multicellular 2017). SUMO2 and SUMO3 are nearly identi- organisms. cal and resemble approximately 50% to SUMO1 (Geiss-Friedlander et al., 2007). Precursors of ubiquitin and SUMO are pro- Posttranslational modifcations cessed to mature forms prior to conjugation and in regulation of cellular activated by an E1 enzyme in a reaction depend- processes ing on ATP. Subsequently ubiquitin and SUMO are transferred to an E2 enzyme, and E3 ligase General principles of ubiquitination alone or with E2 ligates them to substrates by and SUMOylation an (Hershko et al., 1998; Hay, Postranslational modifcation (PTM) of pro- 2013). Modifcation is reversible and specifc teins is a powerful, fast and ofen transient way proteases can cleave ubiquitin and SUMO from to control the fate of existing proteins and cell substrates (Williamson et al., 2013; Kunz et al., caister.com/cimb 99 Curr. Issues Mol. Biol. Vol. 35 304 | Sundvall

2018). Proteins can be tagged by a single ubiqui- E1 (Sae1/Aos1–Sae2/Uba2) and E2 (Ubc9) tin or SUMO either at one or at multiple . are known to be involved in SUMO conjugation In addition, modifcations can exist as chains. (Hay, 2013). Tree classes of SUMO E3s have Ubiquitin contains seven internal lysine residues been widely accepted and characterized including (K6, K11, K27, K29, K33, K48, K63) that are SP-RING Siz/PIAS ligases, RanBP2 and ZNF451 involved in the formation of ubiquitin-ubiquitin ligases (Geiss-Friedlander et al., 2007; Rytinki et polymers, known as polyubiquitin chains (Pickart al., 2009; Cappadocia et al., 2015). Both E2 and et al., 2004; Heride et al., 2014). In addition, the E3 can select substrates for SUMOylation, and linkage between the amino-terminal amino group spatial and temporal regulation of co-localization of on a ubiquitin can be conjugated appears integral for substrate selection (Pichler with a target protein and the carboxy-terminal et al., 2017). proteases of the sentrin- carboxy group of the incoming ubiquitin for specifc protease (SENP) family members reverse linear chains (Walczak et al., 2012). SUMOs SUMO conjugation in mammals (Kunz et al., can also form polymeric chains through internal 2018). Moreover, desumoylating isopeptides 1 lysine residues (Geiss-Friedlander et al., 2007). and 2 and ubiquitin-specifc protease-like 1 can Monoubiquitination and diferent chain types deSUMOylate proteins (Shin et al., 2012; Schulz et determine the fate of the modifed protein (Piper al., 2012). Whereas ubiquitin machinery is widely et al., 2014). For example, K48 ubiquitin chains expressed within a cell, components of SUMO are considered classical signals for proteasomal conjugation pathway mainly localize at the nuclear degradation and K63 ubiquitin chains are linked pores and nucleus. Tus, most of SUMOylated to trafcking and DNA damage response (Pick- substrates are nuclear proteins, although SUMO art et al., 2004). Recently basic principles of the modifed proteins outside of nucleus exist (Geiss- feld have been challenged by e.g. discoveries of Friedlander et al., 2007). mixed polyubiquitin chains and ubiquitination of Ubiquitination is regulated by extracellular non-lysine residues (Piper et al., 2014). Less is stimuli including growth factors and cytokines, known regarding the consequences of atachment stress and changes (Pickart et al., 2004; of either single or many SUMO moieties. SUMO Heride et al., 2014). Diferent types of stress stimuli chains are at least implicated in recruitment of such as heat shock, hypoxia, reactive oxygen spe- SUMO-targeted ubiquitin ligases (Lallemand- cies, DNA damage and proteotoxic stress regulate Breitenbach et al., 2008). the activity of SUMOylation machinery (Hieta- kangas et al., 2003; Shao et al., 2004; Bossis et al., Components, regulation and function 2006; Galanty et al., 2009; Morris et al., 2009; of ubiquitin and SUMO machinery Seifert et al., 2015). Both ubiquitin and SUMO Multiple enzymes involved in ubiquitin conjuga- modifcations can alter the function, activity, loca- tion have been recognized. Te human ubiquitin tion and stability of their targets. Ubiquitin and machinery comprises a network including two SUMO are recognized by either ubiquitin-binding ubiquitin E1 enzymes, approximately 40 ubiquitin domains (UBD) or sumo-interacting domains E2s, and more than 600 E3 ubiquitin ligases in (SIM), respectively, and serve as platforms for the human (Heride et al., 2014). Tree non-covalent protein–protein interactions (Seet major types of E3 ligases are really interesting et al., 2006). Tese domains have been identi- new (RING) type E3s comprising most fed in hundreds of proteins. PTMs are also of human E3s, homologous to E6-AP carboxyl involved in regulation of conjugation specifcity terminus (HECT) and RING-between-RING and activation (Pichler et al., 2017). For example, (RBR) E3s ligases (Deshaies et al., 2009; Rotin SUMO-targeted (STUbL) RNF4 et al., 2009; Wenzel et al., 2012). Ubiquitin is contains multiple SIMs and a RING-domain to cleaved by approximately 100 deubiquitinating bind SUMOylated proteins and an E2 ubiquitin- enzymes (DUBs) (Williamson et al., 2013; Heride conjugation enzyme (Sun et al., 2007; Tatham et et al., 2014). Intriguingly, only one heterodimeric al., 2008).

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Ubiquitin and SUMO as signals and endosomal sortin complex required for regulating membrane trafcking transport (ESCRT) (Piper et al., 2014). Ubiquitin and is also indirectly involved in control of endocytosis as components of endocytic machinery are actively General principles of membrane regulated by ubiquitination (Piper et al., 2014). protein trafcking and endocytosis in SUMOylation has been implicated in the cells regulation of endocytic processes, although Internalization and endocytosis of cell surface when compared to ubiquitin the evidence is less proteins including diferent receptors ofen occurs extensive, and more work is needed to make general via the clathrin-dependent endocytic pathway. conclusions. Nevertheless, endocytosis of kainate Cell surface receptors are clustered to pits coated GluR6 is regulated by SUMOylation with clathrin that pinch of of the membrane and non-SUMOylated mutant of GluR6, GluR6- forming vesicles and early . From early K886R, is endocytosis-impaired due to unknown endosomes cargo can be directed back to plasma mechanisms (Martin et al., 2007). SUMOylation membrane via recycling endosomes or destined to of Smoothened (Smo) promotes its localization lysosomal degradation via late endosomes and mul- at the cell surface (Ma et al., 2016). Intriguingly, tivesicular bodies (Mellman and Yarden, 2013). mechanistically SUMO interferes with efcient Smo Also, other types of endocytic routes exist, includ- ubiquitination by recruiting deubiquitinase UBPY/ ing cholesterol-rich membrane structures, such USP8 in a SIM-dependent manner (Ma et al., 2016). as lipid rafs and caveolae (Barbieri et al., 2016). SUMOylation regulates also cell surface expression Several adaptor proteins and PTMs control these and activity of VEGFR2 receptor processes (Piper et al., 2014). Membrane protein (Zhou et al., 2018). VEGFR2–SUMO1 fusion trafcking and endocytosis system are tightly con- protein but not SUMOylation defective mutant nected to protein homeostasis. VEGFR2 accumulated at the Golgi suggesting that mechanistically SUMO regulates exocytosis Ubiquitin and SUMO in receptor of VEGFR (Zhou et al., 2018). SUMOylation can internalization at the cell surface and also indirectly regulate endocytosis. Components in endocytic compartments of endocytic machinery are modifed and regulated Initial studies in yeast suggested that ubiquitin can by SUMO, such as CIN85 (Tossidou et al., 2012) function as a sorting signal regulating the inter- and arrestin (Wyat et al., 2011). Interestingly, also nalization and endosomal targeting of cell surface dynamin interacts with several members of the receptors (Kölling et al., 1994; Hicke et al. 1996, SUMOylation machinery (Mishra et al., 2004). Terrell et al., 1998). Afer that several studies in dif- Moreover, SUMO can be important for membrane ferent systems and organisms have confrmed that binding of proteins. SUMOylation of PTEN at ubiquitin is important regulator of endocytosis and lysine 266 within CBR3 loop fosters binding its most critical functional role is likely at the sorting of PTEN to plasma membrane via electrostatic endosomes (Mellman and Yarden, 2013). Endocy- interactions (Huang et al., 2012). tosis of human receptor tyrosine (RTKs) is suggested to be regulated by multimonoubiquitina- tion and K63-polyubiquitination, and there is some Ubiquitin and SUMO as signals controversy regarding the signifcance of specifc regulating nucleocytoplasmic ubiquitination type due to methodological chal- shuttling and subnuclear lenges to address this complex regulatory system targeting (Haglund et al., 2003; McCullough et al., 2004; Huang et al., 2006; Sundvall et al., 2008; Huang et General principles of nuclear import, al., 2013). During endocytosis the ubiquitin moie- subnuclear targeting and export ties of cargo are recognized by diferent endocytic Passage of proteins in and out of the nucleus adaptors and regulators via UBDs, such as Eps15, through nuclear pore complexes is tightly regulated.

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In principle, many of the nuclear proteins contain SUMO has been suggested to regulate nuclear nuclear localization signal (NLS) and nuclear export of some proteins, including transcriptional export signal (NES) that facilitate trafcking via repressor TEL, Kruppel-like factor associations with karyopherins including importins (KLF2), hydroxylmethyltransferase 1 and exportins (CRM1) together with Ran-GTP, (SHMT1), PTEN, , ErbB4 and Notch (Wood respectively (Stewart M, 2007). et al., 2003; Du et al., 2008, Anderson et al., 2009; Bassi et al., 2013, Santiago et al., 2013, Knitle Ubiquitin and SUMO in nuclear et al., 2017; Antila et al., 2018). SUMOylation targeting and trapping adjacent to NES of KLF5 interferes with its Molecular mechanism by which ubiquitin machin- interaction with nuclear export receptor CRM1 ery controls protein functions are very complex resulting in the inhibition of efcient export but, nevertheless, some evidence exists to sug- and increased accumulation in the nucleus (Du gest the role for ubiquitin as a signal controlling et al., 2008). ErbB4 RTK undergoes regulated nucleocytoplasmic trafcking. Ubiquitination of intramembrane (RIP) releasing an p53 contributes to nuclear export, and although intracellular domain (ICD) that can translocate the regulation of p53 ubiquitination and trafcking to nucleus and regulate transcription. PIAS3 has turned out to be very complicated and likely catalysed SUMOylation within NES of ErbB4 dependent of conditions, atachment of mon- increases the nuclear accumulation of a tyrosine oubiquitin in particular is suggested to play a role phosphorylated ICD by altering the interaction in trafcking (Lohrum et al., 2001; Li et al., 2003). with CRM1 (Sundvall et al., 2012; Knitle et al., Moreover, similar type of regulation has been sug- 2017). SUMOylation defcient mutant of ErbB4 gested for another tumour suppressor protein, accumulates less in nucleus and cannot convey PTEN and NF-kB essential modulator NEMO efciently nuclear signalling (Knitle et al., 2017). (Huang et al., 2003; Trotman et al., 2007). Another receptor undergoing RIP, Notch, is also SUMO was initially discovered as a modifer SUMOylated in the nucleus and SUMOylation of RanGap1 targeting it to nuclear pore complex increases nuclear accumulation of the ICD, but (Matunis et al., 1996, Mahajan et al., 1997). Later mechanisms resulting in accumulation remain to SUMO has been implicated in both increasing and be elucidated (Antila et al., 2018). SUMOylation decreasing the nuclear accumulation of some pro- of SHMT1 increases nuclear accumulation and teins. Mechanistically, covalent linkage of SUMO of the SUMO motif prevents transloca- may directly block protein interactions relevant for tion to the nucleus due to unknown mechanisms transport or generate SIM-mediated interaction (Anderson DD et al., 2009). Interestingly, same platform facilitating or interfering with transport. sites are also ubiquitinated with K63 polyubiq- SUMOylation is suggested to regulate nuclear uitin chains increasing stability in the nucleus import of full-length IGF receptor (Sehat et al., (Anderson et al., 2012). SUMOylation of PTEN 2010). Te levels of SUMOylation defective mutant (at K254) is suggested to regulate the efcient IGFR are similar at the cell surface compared with nuclear accumulation and subsequently DNA wild type receptor, but the mutant receptor cannot damage response. When compared to wild type, translocate to nucleus unlike wild type (Sehat et al., SUMOylation defcient mutant of PTEN local- 2010). Specifcally IGFR is suggested to interact izes less into the nucleus and cannot efciently with RanBP2 at nuclear pores and that RanBP2 regulate homologous recombination (Bassi et acts as an SUMO E3 ligase for IGFR (Pancham al., 2013). Nucleocytoplasmic distribution of et al., 2015). SUMOylation may also increase the SUMOylation-defcient transcriptional repressor stability of IGFR (Pancham et al., 2015). Trafck- TEL also changes compared to wild type (Wood ing of SUMO machinery components is also under et al., 2003). However, the direct mechanism how the control of SUMO. SUMOylation of Sae2 in SUMO regulates subcellular localization of PTEN the c-terminus within functional NLS efciently or TEL is not clear (Wood et al., 2003; Bassi et increases nuclear accumulation (Truong et al., al., 2013). On the contrary, SUMOylation of p53 2012). stimulates its nuclear export by increasing the

caister.com/cimb 102 Curr. Issues Mol. Biol. Vol. 35 Ubiquitin and SUMO in Intracellular Trafcking | 307 disassembly of p53 from the CRM1 in the and regulation of transcription (Finkbeiner et al., (Santiago et al. 2013). Moreover, SUMOylation 2011). regulates nuclear export and intranuclear distribu- tion of adenovirus E1B-55K protein (Kindsmüller et al., 2007). Altogether nuclear export and The genetic evidence in vivo and SUMOylation appear to be closely connected due the signifcance of ubiquitin and to CRM1-mediated interaction of export com- SUMO mediated regulation of plexes with SUMO E3 ligase RanBP2 (Riterhof trafcking in human diseases et al., 2015) and SUMOylation also regulates Genetic studies using targeted gene disruption in nuclear transport via covalent modifcation of mice suggest that ubiquitin and SUMO pathways transport machinery (Rothenbusch et al., 2012). are essential, but a lot of redundancy is evident with many of the pathway components. For example, Regulation of subnuclear targeting SUMO1 and SUMO3 knockout mice are viable, by ubiquitin and SUMO but SUMO2 knockout mice die during embryo- Ubiquitin and SUMO system has been indicated genesis as well as Ubc9 knockout is lethal in mice in targeting proteins into certain subnuclear struc- (Nacerddine et al., 2005; Evdokimov et al., 2008; tures. Subnuclear targeting can direct proteins into Zhang et al., 2008; Wang et al., 2014). Unfortu- locations essential for their functions, trap protein nately, very litle is known regarding genetic models in locations where they are not available to regulate of modifcation-defcient mutants and their pheno- e.g. transcription or alter their susceptibility to types in vivo. regulators of stability. Both ubiquitin and SUMO Deregulation of ubiquitin conjugation are implicated in correct targeting of DNA repair machinery and altered protein ubiquitination has factors to the sites of DNA damage (Ulrich, 2014). been reported in diseases such as neurodegen- For example, BRCA1 targeting to double-strand erative diseases and cancer (Popovic et al., 2014). breaks is regulated by K63-linked ubiquitina- SUMOylation seems to be a general protective tion and SUMO and the process involves RNF4 mechanism against the damage caused by stresses (Galanty et al., 2009; Morris et al., 2009; Guzzo et such as low oxygen and nutrient deprivation al., 2012). PML bodies are subnuclear structures and may also protect afer stress and involved in regulation of transcription and host a lot support the growth of cancer cells. of transcription factors and their regulators (Zhong targeting ubiquitin conjugation machinery, such et al., 2000a). PML is strongly SUMOylated and as E3 ligases, and somatic mutations altering SUMOylation regulates the integrity of PML ubiquitin ligase binding and subsequent trafck- bodies and stability of PML as SUMOylation def- ing of targets, including deregulated endocytosis cient mutant PML does not form of RTKs, in cancer have been reported (Mellman when expressed in PML null cells (Ishov et al., and Yarden, 2013). SUMOylation seems to be 1999; Müller et al., 1998; Zhong et al., 2000a,b). up-regulated in cancer due to e.g. overexpression Several nuclear proteins are hosted in PML bodies of the pathway components, such as Ubc9 and and SIM-mediated interactions are thought to be some E3 ligases (Seeler et al., 2017). Interestingly, important for assembly (Shen et al., 2006). SUMO it has been reported that the SUMOylation site is E3 ligases and deSUMOlases have specifc nuclear essential for leukaemic transformation mediated by localizations and regulate substrate localization, but PML-RRalpha in acute promyelocytic leukaemia regulation is ofen not SUMO-dependent (Sachdev (Zhu et al., 2005). Moreover, a germline variant of et al., 2001; Kotaja et al., 2002; Hietakangas et al., melanoma lineage-specifc microphthalmia-associ- 2003). On the other hand, SUMO is suggested ated transcription factor (MITF), MITF-E318K, to be important in the regulation of subnuclear increases predisposition to sporadic melanoma localization of Nuclear Factor of Activated T-cells and renal cell carcinoma. Tis mutation disrupts (NFAT1) (Terui et al., 2004) or nucleolar localiza- SUMOylation site of MITF and results in increased tion of -, - and leucine-rich transcriptional activity promoting tumourigenic protein 1 (PELP1) involved in properties in experimental models, but no changes

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