Skip to main content
SpringerLink
Log in

The Molecular Interface Between the SUMO and Ubiquitin Systems

  • Chapter
  • First Online:
Book cover SUMO Regulation of Cellular Processes

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 963))

Abstract

The SUMO conjugation system regulates key cellular processes including cell growth, division, mitochondrial dynamics, and the maintenance of genome stability in eukaryotic cells. The ubiquitin conjugation system regulates the stability of a myriad of vital cellular proteins in a signal-dependent manner by targeting them for destruction via the proteasome-mediated degradation pathway. Recent research efforts have unveiled an evolutionarily conserved and fundamental molecular interface between the SUMO and ubiquitin systems. A coordinated and integrated interaction between these two pathways plays a key role in adapting the SUMO-related stress response to alterations in sub-cellular protein localization, specific protein recruitment strategies, and the regulation of stress-inducible protein stability. This chapter will describe the interconnected and interdependent role of the SUMO and ubiquitin systems in mediating DNA damage repair and the genesis and the resolution of inflammatory-related diseases such as cancer. New insights regarding the interdependence of these two important post-translational modifications with nuclear receptor superfamily members will also be highlighted.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Aitken AE, Richardson TA, Morgan ET (2006) Regulation of drug-metabolizing enzymes and transporters in inflammation. Annu Rev Pharmacol Toxicol 46:123–149

    Article  CAS  PubMed  Google Scholar 

  • Baumann H, Gauldie J (1994) The acute phase response. Immunol Today 15:74–80

    Article  CAS  PubMed  Google Scholar 

  • Borden KL, Freemont PS (1996) The RING finger domain: a recent example of a sequence-structure family. Curr Opin Struct Biol 6:395–401

    Article  CAS  PubMed  Google Scholar 

  • Bruderer R, Tatham MH, Plechanovova A, Matic I, Garg AK, Hay RT (2011) Purification and identification of endogenous polySUMO conjugates. EMBO Rep 12:142–148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burgess RC, Rahman S, Lisby M, Rothstein R, Zhao XL (2007) The slx5-slx8 complex affects sumoylation of DNA repair proteins and negatively regulates recombination. Mol Cell Biol 27:6153–6162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng J, Shah YM, Gonzalez FJ (2012) Pregnane X receptor as a target for treatment of inflammatory bowel disorders. Trends Pharmacol Sci 33:323–330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chiariotti L, Benvenuto G, Fedele M, Santoro M, Simeone A, Fusco A, Bruni CB (1998) Identification and characterization of a novel RING-finger gene (RNF4) mapping at 4p16.3. Genomics 47:258–265

    Article  CAS  PubMed  Google Scholar 

  • Cui W, Sun M, Galeva N, Williams TD, Azuma Y, Staudinger JL (2015) SUMOylation and ubiquitylation circuitry controls pregnane X receptor biology in hepatocytes. Drug Metab Dispos 43:1316–1325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cui W, Sun M, Zhang S, Shen X, Galeva N, Williams TD, Staudinger JL (2016) A SUMO-acetyl switch in PXR biology. Biochim Biophys Acta. doi:10.1016/j.bbagrm.2016.12.015

    Google Scholar 

  • Dennis AP, O’Malley BW (2005) Rush hour at the promoter: how the ubiquitin-proteasome pathway polices the traffic flow of nuclear receptor-dependent transcription. J Steroid Biochem Mol Biol 93:139–151

    Article  CAS  PubMed  Google Scholar 

  • Desterro JM, Rodriguez MS, Hay RT (1998) SUMO-1 modification of IkappaBalpha inhibits NF-kappaB activation. Mol Cell 2:233–239

    Article  CAS  PubMed  Google Scholar 

  • Dou W, Mukherjee S, Li H, Venkatesh M, Wang H, Kortagere S, Peleg A, Chilimuri SS, Wang ZT, Feng Y, Fearon ER, Mani S (2012) Alleviation of gut inflammation by Cdx2/Pxr pathway in a mouse model of chemical colitis. PLoS One 7:e36075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Galanty Y, Belotserkovskaya R, Coates J, Jackson SP (2012) RNF4, a SUMO-targeted ubiquitin E3 ligase, promotes DNA double-strand break repair. Genes Dev 26:1179–1195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Geoffroy MC, Jaffray EG, Walker KJ, Hay RT (2010) Arsenic-induced SUMO-dependent recruitment of RNF4 into PML nuclear bodies. Mol Biol Cell 21:4227–4239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ghisletti S, Huang W, Ogawa S, Pascual G, Lin ME, Willson TM, Rosenfeld MG, Glass CK (2007) Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARgamma. Mol Cell 25:57–70

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Groocock LM, Nie M, Prudden J, Moiani D, Wang T, Cheltsov A, Rambo RP, Arvai AS, Hitomi C, Tainer JA, Luger K, Perry JJ, Lazzerini-Denchi E, Boddy MN (2014) RNF4 interacts with both SUMO and nucleosomes to promote the DNA damage response. EMBO Rep 15:601–608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guo BQ, Sharrocks AD (2009) Extracellular signal-regulated kinase mitogen-activated protein kinase signaling initiates a dynamic interplay between sumoylation and ubiquitination to regulate the activity of the transcriptional activator PEA3. Mol Cell Biol 29:3204–3218

    Article  CAS  PubMed  Google Scholar 

  • Guzzo CM, Berndsen CE, Zhu J, Gupta V, Datta A, Greenberg RA, Wolberger C, Matunis MJ (2012) RNF4-dependent hybrid SUMO-ubiquitin chains are signals for RAP80 and thereby mediate the recruitment of BRCA1 to sites of DNA damage. Sci Signal 5:ra88

    Article  PubMed  PubMed Central  Google Scholar 

  • Hakli M, Karvonen U, Janne OA, Palvimo JJ (2001) The RING finger protein SNURF is a bifunctional protein possessing DNA binding activity. J Biol Chem 276:23653–23660

    Article  CAS  PubMed  Google Scholar 

  • Hannich JT, Lewis A, Kroetz MB, Li SJ, Heide H, Emili A, Hochstrasser M (2005) Defining the SUMO-modified proteome by multiple approaches in Saccharomyces cerevisiae. J Biol Chem 280:4102–4110

    Article  CAS  PubMed  Google Scholar 

  • Hay RT (2013) Decoding the SUMO signal. Biochem Soc Trans 41:463–473

    Article  CAS  PubMed  Google Scholar 

  • Hecker CM, Rabiller M, Haglund K, Bayer P, Dikic I (2006) Specification of SUMO1- and SUMO2-interacting motifs. J Biol Chem 281:16117–16127

    Article  CAS  PubMed  Google Scholar 

  • Hoege C, Pfander B, Moldovan GL, Pyrowolakis G, Jentsch S (2002) RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature 419:135–141

    Article  CAS  PubMed  Google Scholar 

  • Hu G, Xu CS, Staudinger JL (2010) Pregnane X receptor Is SUMOylated to repress the inflammatory response. J Pharmacol Exp Ther 335:342–350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang TT, Wuerzberger-Davis SM, Wu ZH, Miyamoto S (2003) Sequential modification of NEMO/IKK gamma by SUMO-1 and ubiquitin mediates NF-kappa B activation by genotoxic stress. Cell 115:565–576

    Article  CAS  PubMed  Google Scholar 

  • Hunter T, Sun H (2008) Crosstalk between the SUMO and ubiquitin pathways. Ernst Schering Found Symp Proc 1–16

    Google Scholar 

  • Ii T, Fung J, Mullen JR, Brill SJ (2007a) The yeast Slx5-Slx8 DNA integrity complex displays ubiquitin ligase activity. Cell Cycle 6:2800–2809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ii T, Mullen JR, Slagle CE, Brill SJ (2007b) Stimulation of in vitro sumoylation by Slx5-Slx8: evidence for a functional interaction with the SUMO pathway. DNA Repair 6:1679–1691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson ES (2004) Protein modification by SUMO. Annu Rev Biochem 73:355–382

    Article  CAS  PubMed  Google Scholar 

  • Kacevska M, Robertson GR, Clarke SJ, Liddle C (2008) Inflammation and CYP3A4-mediated drug metabolism in advanced cancer: impact and implications for chemotherapeutic drug dosing. Expert Opin Drug Metab Toxicol 4:137–149

    Article  CAS  PubMed  Google Scholar 

  • Keith B, Johnson RS, Simon MC (2012) HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 12:9–22

    CAS  Google Scholar 

  • Kim DH, Xiao Z, Kwon S, Sun X, Ryerson D, Tkac D, Ma P, Wu SY, Chiang CM, Zhou E, Xu HE, Palvimo JJ, Chen LF, Kemper B, Kemper JK (2015) A dysregulated acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity. EMBO J 34:184–199

    Article  PubMed  Google Scholar 

  • Kliewer SA, Goodwin B, Willson TM (2002) The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism. Endocr Rev 23:687–702

    Article  CAS  PubMed  Google Scholar 

  • Lallemand-Breitenbach V, Jeanne M, Benhenda S, Nasr R, Lei M, Peres L, Zhou J, Zhu J, Raught B, de The H (2008) Arsenic degrades PML or PML – RAR alpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway. Nat Cell Biol 10:547–555

    Article  CAS  PubMed  Google Scholar 

  • Lallemand-Breitenbach V, Zhu J, Chen Z, de The H (2012) Curing APL through PML/RARA degradation by As2O3. Trends Mol Med 18:36–42

    Article  CAS  PubMed  Google Scholar 

  • Lescasse R, Pobiega S, Callebaut I, Marcand S (2013) End-joining inhibition at telomeres requires the translocase and polySUMO-dependent ubiquitin ligase Uls1. EMBO J 32:805–815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liew CW, Sun H, Hunter T, Day CL (2010) RING domain dimerization is essential for RNF4 function. Biochem J 431:23–29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lonard DM, O’Malley BW (2009) Emerging roles of the ubiquitin proteasome system in nuclear hormone receptor signaling. Prog Mol Biol Transl Sci 87:117–135

    Article  CAS  PubMed  Google Scholar 

  • Lovering R, Hanson IM, Borden KL, Martin S, O’Reilly NJ, Evan GI, Rahman D, Pappin DJ, Trowsdale J, Freemont PS (1993) Identification and preliminary characterization of a protein motif related to the zinc finger. Proc Natl Acad Sci U S A 90:2112–2116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martin N, Schwamborn K, Schreiber V, Werner A, Guillier C, Zhang XD, Bischof O, Seeler JS, Dejean A (2009) PARP-1 transcriptional activity is regulated by sumoylation upon heat shock. EMBO J 28:3534–3548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Minty A, Dumont X, Kaghad M, Caput D (2000) Covalent modification of p73 alpha by SUMO-1 – Two-hybrid screening with p73 identifies novel SUMO-1-interacting proteins and a SUMO-1 interaction motif. J Biol Chem 275:36316–36323

    Article  CAS  PubMed  Google Scholar 

  • Moilanen AM, Poukka H, Karvonen U, Hakli M, Janne OA, Palvimo JJ (1998) Identification of a novel RING finger protein as a coregulator in steroid receptor-mediated gene transcription. Mol Cell Biol 18:5128–5139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morgan ET, Goralski KB, Piquette-Miller M, Renton KW, Robertson GR, Chaluvadi MR, Charles KA, Clarke SJ, Kacevska M, Liddle C, Richardson TA, Sharma R, Sinal CJ (2008) Regulation of drug-metabolizing enzymes and transporters in infection, inflammation, and cancer. Drug Metab Dispos 36:205–216

    Article  CAS  PubMed  Google Scholar 

  • Mukhopadhyay D, Arnaoutov A, Dasso M (2010) The SUMO protease SENP6 is essential for inner kinetochore assembly. J Cell Biol 188:681–692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mullen JR, Brill SJ (2008) Activation of the Slx5-Slx8 ubiquitin ligase by poly-small ubiquitin-like modifier conjugates. J Biol Chem 283:19912–19921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nie M, Boddy MN (2016) Cooperativity of the SUMO and Ubiquitin Pathways in Genome Stability. Biomolecules 6:14

    Article  PubMed  PubMed Central  Google Scholar 

  • Pascual G, Fong AL, Ogawa S, Gamliel A, Li AC, Perissi V, Rose DW, Willson TM, Rosenfeld MG, Glass CK (2005) A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature 437:759–763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Percherancier Y, Germain-Desprez D, Galisson F, Mascle XH, Dianoux L, Estephan P, Chelbi-Alix MK, Aubry M (2009) Role of SUMO in RNF4-mediated promyelocytic leukemia protein (PML) degradation: sumoylation of PML and phospho-switch control of its SUMO binding domain dissected in living cells. J Biol Chem 284:16595–16608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perry JJP, Tainer JA, Boddy MN (2008) A SIM-ultaneous role for SUMO and ubiquitin. Trends Biochem Sci 33:201–208

    Article  CAS  PubMed  Google Scholar 

  • Plechanovova A, Jaffray EG, McMahon SA, Johnson KA, Navratilova I, Naismith JH, Hay RT (2011) Mechanism of ubiquitylation by dimeric RING ligase RNF4. Nat Struct Mol Biol 18:1052–1059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Plechanovova A, Jaffray EG, Tatham MH, Naismith JH, Hay RT (2012) Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis. Nature 489:115–120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prudden J, Pebernard S, Raffa G, Slavin DA, Perry JJP, Tainer JA, McGowan CH, Boddy MN (2007) SUMO-targeted ubiquitin ligases in genome stability. EMBO J 26:4089–4101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schimmel J, Larsen KM, Matic I, van Hagen M, Cox J, Mann M, Andersen JS, Vertegaal ACO (2008) The ubiquitin-proteasome system is a key component of the SUMO-2/3 cycle. Mol Cell Proteomics 7:2107–2122

    Article  CAS  PubMed  Google Scholar 

  • Serhan CN, Chiang N, Van Dyke TE (2008) Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol 8:349–361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song J, Durrin LK, Wilkinson TA, Krontiris TG, Chen YA (2004) Identification of a SUMO-binding motif that recognizes SUMO-modified proteins. Proc Natl Acad Sci U S A 101:14373–14378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sriramachandran AM, Dohmen RJ (2014) SUMO-targeted ubiquitin ligases. Biochim Biophys Acta 1843:75–85

    Article  CAS  PubMed  Google Scholar 

  • Staudinger JL (2013) Disease, drug metabolism, and transporter interactions. Pharmacol Res 30:2171–2173

    Article  CAS  Google Scholar 

  • Staudinger JL, Madan A, Carol KM, Parkinson A (2003) Regulation of drug transporter gene expression by nuclear receptors. Drug Metab Dispos 31:523–527

    Article  PubMed  Google Scholar 

  • Staudinger JL, Ding X, Lichti K (2006) Pregnane X receptor and natural products: beyond drug-drug interactions. Expert Opin Drug Metab Toxicol 2:847–857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Staudinger JL, Xu C, Biswas A, Mani S (2011) Post-translational modification of pregnane x receptor. Pharmacol Res 64:4–10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun H, Leverson JD, Hunter T (2007) Conserved function of RNF4 family proteins in eukaryotes: targeting a ubiquitin ligase to SUMOylated proteins. EMBO J 26:4102–4112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun M, Cui W, Woody SK, Staudinger JL (2015) Pregnane X receptor modulates the inflammatory response in primary cultures of hepatocytes. Drug Metab Dispos 43:335–343

    Article  PubMed  PubMed Central  Google Scholar 

  • Tatham MH, Geoffroy MC, Shen L, Plechanovova A, Hattersley N, Jaffray EG, Palvimo JJ, Hay RT (2008) RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nat Cell Biol 10:538–546

    Article  CAS  PubMed  Google Scholar 

  • Ulrich HD (2005) Mutual interactions between the SUMO and ubiquitin systems: a plea of no contest. Trends Cell Biol 15:525–532

    Article  CAS  PubMed  Google Scholar 

  • Uzunova K, Gottsche K, Miteva M, Weisshaar SR, Glanemann C, Schnellhardt M, Niessen M, Scheel H, Hofmann K, Johnson ES, Praefcke GJ, Dohmen RJ (2007) Ubiquitin-dependent proteolytic control of SUMO conjugates. J Biol Chem 282:34167–34175

    Article  CAS  PubMed  Google Scholar 

  • van Hagen M, Overmeer RM, Abolvardi SS, Vertegaal ACO (2010) RNF4 and VHL regulate the proteasomal degradation of SUMO-conjugated Hypoxia-Inducible Factor-2 alpha. Nucleic Acids Res 38:1922–1931

    Article  PubMed  Google Scholar 

  • Wang Z, Jones GM, Prelich G (2006) Genetic analysis connects SLX5 and SLX8 to the SUMO pathway in Saccharomyces cerevisiae. Genetics 172:1499–1509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weisshaar SR, Keusekotten K, Krause A, Horst C, Springer HM, Gottsche K, Dohmen J, Praefcke GJK (2008) Arsenic trioxide stimulates SUMO-2/3 modification leading to RNF4-dependent proteolytic targeting of PML. FEBS Lett 582:3174–3178

    Article  CAS  PubMed  Google Scholar 

  • Xie Y, Kerscher O, Kroetz MB, McConchie HF, Sung P, Hochstrasser M (2007) The yeast HEX3-SLX8 heterodimer is a ubiquitin ligase stimulated by substrate sumoylation. J Biol Chem 282:34176–34184

    Article  CAS  PubMed  Google Scholar 

  • Yang L, Mullen JR, Brill SJ (2006) Purification of the yeast Slx5-Slx8 protein complex and characterization of its DNA-binding activity. Nucleic Acids Res 34:5541–5551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yin YL, Seifert A, Chua JS, Maure JF, Golebiowski F, Hay RT (2012) SUMO-targeted ubiquitin E3 ligase RNF4 is required for the response of human cells to DNA damage. Genes Dev 26:1196–1208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang C, Roberts TM, Yang J, Desai R, Brown GW (2006) Suppression of genomic instability by SLX5 and SLX8 in Saccharomyces cerevisiae. DNA Repair 5:336–346

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pharmacology and Toxicology, University of Kansas, Lawrence, KS, 66045, USA

    Jeff L. Staudinger

Authors
  1. Jeff L. Staudinger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeff L. Staudinger .

Editor information

Editors and Affiliations

  1. Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M Health Science Center, Bryan, Texas, USA

    Van G. Wilson

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Staudinger, J.L. (2017). The Molecular Interface Between the SUMO and Ubiquitin Systems. In: Wilson, V. (eds) SUMO Regulation of Cellular Processes. Advances in Experimental Medicine and Biology, vol 963. Springer, Cham. https://doi.org/10.1007/978-3-319-50044-7_6

Download citation

Publish with us

Policies and ethics

Search

Navigation