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The SUMO Conjugation Complex Self-Assembles Into Nuclear Bodies

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The SUMO Conjugation Complex Self-Assembles Into Nuclear Bodies bioRxiv preprint doi: https://doi.org/10.1101/393272; this version posted August 22, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Short title: SUMO conjugation activity in nuclear bodies 2 Corresponding Author: Dr. Harrold A. van den Burg 3 Molecular Plant Pathology 4 SILS, University of Amsterdam 5 Science Park 904 6 1098XH, Amsterdam 7 the Netherlands 8 Tel. +31 (0)20 525 7797 9 Title: 10 The SUMO conjugation complex self-assembles into 11 nuclear bodies independent of SIZ1 and COP1 12 13 Authors: 14 Magdalena J. Mazur1,3¶, Mark Kwaaitaal1¶, Manuel Arroyo Mateos1, Francesca 15 Maio1, Ramachandra K. Kini1,4, Marcel Prins1,2 and Harrold A. van den Burg1,* 16 17 Author affiliations: 18 ¶Authors contributed equally to this Work. 19 1Molecular Plant Pathology, Swammerdam Institute for Life Sciences (SILS), 20 University of Amsterdam, 21 2Keygene N.V., Wageningen, The Netherlands 22 23 One sentence Summary (max 200 characters): 24 SUMO conjugation activity causes formation of SUMO nuclear bodies, Which 25 strongly overlap with COP1 bodies thanks to a substrate-binding (VP) motif in the 26 E3 ligase SIZ1 that acts as bridge protein. 27 1 bioRxiv preprint doi: https://doi.org/10.1101/393272; this version posted August 22, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 28 Footnotes: 29 Author contributions: 30 HB conceptualized the project. MM, MK, FM and HB designed experiments. MM, 31 MK, MAM, FM and RK performed experiments. MM, MK, MA, FM and HB 32 analysed the data. MM, MK and HB Wrote the MS. MM, MK, FM, MAM, MP and 33 HB revieWed and edited the MS. HB and MP acquired funding and supervised the 34 project. MM and MK contributed equally to this Work. 35 36 Funding information: 37 The Netherlands Scientific Organisation (ALW-VIDI grant 864.10.004 to HvdB) and 38 the Topsector T&U program Better Plants for Demands (grant 1409-036 to HvdB), 39 including the partnering breeding companies, supported this Work; FM is financially 40 supported by Keygene N.V. (The Netherlands). 41 42 Current address: 43 3Current address: Laboratory of Virology, Wageningen University, Wageningen, 44 The Netherlands 45 4Current address: Department of Studies in Biotechnology, University of Mysore, 46 Manasagangotri, Mysore- 570 006, India 47 48 Corresponding author email: [email protected] 49 2 bioRxiv preprint doi: https://doi.org/10.1101/393272; this version posted August 22, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 50 Abstract 51 Attachment of the small ubiquitin-like modifier SUMO to substrate proteins 52 modulates their turnover, activity or interaction partners. An unresolved question is 53 how this SUMO conjugation activity concentrates the enzymes involved and the 54 substrates into uncharacterized nuclear bodies (NBs). We here define the 55 requirements for the formation of SUMO NBs and for their subsequent co- 56 localisation With the master regulator of groWth, the E3 ubiquitin ligase COP1. COP1 57 activity results in degradation of transcription factors, Which primes the 58 transcriptional response that underlies elongation groWth induced by night-time and 59 high ambient temperatures (skoto- and thermomorphogenesis, respectively). 60 SUMO conjugation activity itself is sufficient to target the SUMO machinery into NBs. 61 Co-localization of these bodies With COP1 requires besides SUMO conjugation 62 activity, a SUMO acceptor site in COP1 and the SUMO E3 ligase SIZ1. We find that 63 SIZ1 docks in the substrate-binding pocket of COP1 via two VP motifs - a knoWn 64 peptide motif of COP1 substrates. The data reveal that SIZ1 physically connects 65 COP1 and SUMO conjugation activity in the same NBs that can also contain the 66 blue-light receptors CRY1 and CRY2. Our findings thus suggest that sumoylation 67 apparently coordinates COP1 activity inside these NBs; a mechanism that 68 potentially explains hoW SIZ1 and SUMO both control the timing and amplitude of 69 the high-temperature groWth response. The strong co-localization of COP1 and 70 SUMO in these NBs might also explain Why many COP1 substrates are sumoylated. 71 72 Word count Abstract: 229 73 74 Word count body text: 7174 75 3 bioRxiv preprint doi: https://doi.org/10.1101/393272; this version posted August 22, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 76 Introduction 77 The post-translational modification of proteins by SUMO1 and -2 (SMALL 78 UBIQUITIN-LIKE MODIFIER 1 and 2) is an essential process in Arabidopsis 79 (Arabidopsis thaliana) affecting hundreds of proteins (Saracco et al., 2007; Miller et 80 al., 2010; Rytz et al., 2018). These two closely related proteins are the nearest 81 homologs of the ancestral SUMO protein (Hammoudi et al., 2016). Their attachment 82 to substrates is catalysed in tWo steps by the SUMO E1 ACTIVATING ENZYME 83 (SAE1/2) dimer and the SUMO E2 CONJUGATING ENZYME (SCE1) (Colby et al., 84 2006; Saracco et al., 2007). SCE1 directly recognizes and conjugates a SUMO 85 moiety to the acceptor lysine embedded in a short consensus motif ΨKxE (Where Ψ 86 denotes a bulky hydrophobic residue, K the acceptor lysine, x any residue, and E is 87 Glutamate) (Bernier-Villamor et al., 2002; Yunus and Lima, 2006). SUMO 88 conjugation (sumoylation) can also be promoted by SUMO E3 ligases, but the 89 conditions by Which E3s are recruited to SCE1 remain unclear (Gareau and Lima, 90 2010). SUMO proteome analyses with human cells suggested that ~25-50% of the 91 SUMO targets are modified at non-consensus sites (Hendriks et al., 2014; 92 Lamoliatte et al., 2017). Structural studies exposed that the E3 ligases orientate the 93 E2 enzyme such that they favour SUMO donor transfer to non-consensus lysines 94 (Yunus and Lima, 2009; Streich and Lima, 2016). Alternatively, substrate selection 95 can involve non-covalent interactions betWeen SUMO and a short hydrophobic 96 peptide in substrates, called the SUMO-interaction motif (SIM) (Zhu et al., 2008; 97 Flotho and Melchior, 2013). SIM peptides bind to SUMO by forming an additional 98 alien β-strand in the β-sheet of SUMO (Song et al., 2005; Hecker et al., 2006; 99 Sekiyama et al., 2008). 100 SUMO often acts as a monomeric adduct, but it can also form SUMO chains 101 (Colby et al., 2006). In yeast and mammals SUMO chains are important signals in 102 meiosis, genome maintenance and (proteotoxic) stress (Vertegaal, 2007; Ulrich, 103 2008; Bruderer et al., 2011; Tatham et al., 2011). These SUMO chains are 104 recognized by SUMO-targeted Ubiquitin E3 ligases (StUbls) that mark the SUMO- 105 modified proteins for degradation (Perry et al., 2008; Guo et al., 2014). Distant 106 homologues of these StUbls Were identified in the Arabidopsis genome, but their 107 biological function remains to be determined (Elrouby et al., 2013). In Arabidopsis, 4 bioRxiv preprint doi: https://doi.org/10.1101/393272; this version posted August 22, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 108 tWo SP-RING domain-containing proteins, PROTEIN INHIBITOR OF ACTIVATED 109 STAT LIKE1 (PIAL1) and PIAL2, Were shoWn to promote SUMO chain formation 110 (Tomanov et al., 2014). There is also a role for the SUMO E2 enzyme in SUMO 111 chain formation (Tomanov et al., 2018). The SUMO E2 interacts via tWo sites with 112 SUMO: (i) a thioester bond (~) between the catalytic cysteine in the E2 and the C- 113 terminal glycine of SUMO (covalent SUMO loading in the catalytic pocket, 114 E2~SUMO) and (ii) a strong nearly constitutive, non-covalent ‘SIM-like’ interaction 115 (non-covalent SUMO binding, SUMO∙E2) (Bencsath et al., 2002; Knipscheer et al., 116 2007; Streich and Lima, 2016). This second non-covalent interaction between 117 SUMO and SCE1 is apparently needed for chain formation, as mutations in the 118 human SUMO E2 enzyme (Ubc9) that disrupt this interaction also strongly reduce 119 SUMO chain formation in vitro (Knipscheer et al., 2007). 120 Many studies on the SUMO (de)conjugation machinery revealed that the 121 SUMO enzymes and their targets often reside in uncharacterized punctate nuclear 122 structures of various shapes and sizes (Murtas et al., 2003; Conti et al., 2008; 123 Cheong et al., 2009; Castaño-Miquel et al., 2013; Xiong and Wang, 2013). The E3 124 ubiquitin ligase CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1), Which is a 125 SUMO substrate, also localizes to nuclear bodies (NBs) (Kim et al., 2016; Lin et al., 126 2016). COP1 is essential for the dark and high-temperature induced groWth 127 responses (skoto- and thermomorphogenesis, respectively) (Lau and Deng, 2012; 128 Park et al., 2017; Hammoudi et al., 2018). Both conditions cause COP1 to 129 translocate from the cytosol to the nucleus Where it localizes to a subclass of NBs 130 (Stacey et al., 1999; Stacey and von Arnim, 1999; Park et al., 2017), Which are 131 proposed sites for degradation of COP1 substrates (Van Buskirk et al., 2012). COP1 132 activity is stimulated by the SUMO E3 ligase SIZ1 and correspondingly both skoto- 133 and thermomorphogenesis are strongly compromised in the SIZ1 null mutant siz1- 134 2 and the knockdoWn mutant sumo1-1;amiR-SUMO2 (Delker et al., 2014; Lin et al., 135 2016; Park et al., 2017; Hammoudi et al., 2018).
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