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Sumoylation in Human Pathogenic Fungi: Role in Physiology and Virulence

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Sumoylation in Human Pathogenic Fungi: Role in Physiology and Virulence Journal of Fungi Review SUMOylation in Human Pathogenic Fungi: Role in Physiology and Virulence Mahima Sagar Sahu 1,2, Sandip Patra 1,2, Kundan Kumar 1,3 and Rupinder Kaur 1,* 1 Laboratory of Fungal Pathogenesis, Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500039, Telangana, India; [email protected] (M.S.S.); [email protected] (S.P.); [email protected] (K.K.) 2 Graduate studies, Regional Centre for Biotechnology, Faridabad 121001, Haryana, India 3 Graduate studies, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India * Correspondence: [email protected] Received: 14 February 2020; Accepted: 3 March 2020; Published: 4 March 2020 Abstract: The small ubiquitin-related modifier (SUMO) protein is an important component of the post-translational protein modification systems in eukaryotic cells. It is known to modify hundreds of proteins involved in diverse cellular processes, ranging from nuclear pore dynamics to signal transduction pathways. Owing to its reversible nature, the SUMO-conjugation of proteins (SUMOylation) holds a prominent place among mechanisms that regulate the functions of a wide array of cellular proteins. The dysfunctional SUMOylation system has been associated with many human diseases, including neurodegenerative and autoimmune disorders. Furthermore, the non-pathogenic yeast Saccharomyces cerevisiae has served as an excellent model to advance our understanding of enzymes involved in SUMOylation and proteins modified by SUMOylation. Taking advantage of the tools and knowledge obtained from the S. cerevisiae SUMOylation system, research on fungal SUMOylation is beginning to gather pace, and new insights into the role of SUMOylation in the pathobiology of medically important fungi are emerging. Here, we summarize the known information on components of the SUMOylation machinery, and consequences of overexpression or deletion of these components in the human pathogenic fungi, with major focus on two prevalent Candida bloodstream pathogens, C. albicans and C. glabrata. Additionally, we have identified SUMOylation components, through in silico analysis, in four medically relevant fungi, and compared their sequence similarity with S. cerevisiae counterparts. SUMOylation modulates the virulence of C. albicans and C. glabrata, while it is required for conidia production in Aspergillus nidulans and A. flavus. In addition to highlighting these recent developments, we discuss how SUMOylation fine tunes the expression of virulence factors, and influences survival of fungal cells under diverse stresses in vitro and in the mammalian host. Keywords: small ubiquitin-like modifier (SUMO); human pathogenic fungi; Candida glabrata; Candida albicans; SUMO-specific proteases and ligases; virulence; stress survival 1. Introduction A reversible post-translational modification of proteins, mediated by a highly conserved small ubiquitin-related modifier (SUMO), regulates numerous physiological processes [1–3]. SUMO is a 11 kDa polypeptide, that is attached covalently, via an isopeptide bond, to the amino group of the ∼ lysine residue in cellular substrate proteins [1,4]. This conjugation is predominantly catalyzed by SUMO ligases, and is the fourth step in the process of SUMOylation [3,5]. The four enzymatic steps in the SUMOylation cascade consist of: (i) SUMO processing by SUMO-specific proteases to generate mature SUMO with an exposed carboxyl-terminal diglycine (GG) motif; (ii) formation of a thioester J. Fungi 2020, 6, 32; doi:10.3390/jof6010032 www.mdpi.com/journal/jof J. Fungi 2020, 6, 32 2 of 19 J. Fungi 2020, 6, x FOR PEER REVIEW 2 of 18 bond between the SUMO-GG motif and the catalytic cysteine residue of the E1-activating enzyme in bond between the SUMO-GG motif and the catalytic cysteine residue of the E1-activating enzyme in an ATP-dependent manner; (iii) transfer of the activated SUMO from the E1-activating enzyme to the an ATP-dependent manner; (iii) transfer of the activated SUMO from the E1-activating enzyme to the E2-conjugating enzyme via a thioester linkage between the cysteine residue of the E2 enzyme and E2-conjugating enzyme via a thioester linkage between the cysteine residue of the E2 enzyme and the the SUMO-GG motif; and (iv) E3 ligase-mediated formation of an isopeptide bond between the SUMO-GG motif; and (iv) E3 ligase-mediated formation of an isopeptide bond between the carboxyl carboxyl group of the C-terminal glycine of the SUMO protein and the ε-amino group of the specific " grouplysine of residue the C-terminal in the target glycine protein of [1,3 the– SUMO5]. These protein SUMOylation and the steps-amino are schematically group of the illustrated specific lysinein residueFigure in 1. the target protein [1,3–5]. These SUMOylation steps are schematically illustrated in Figure1. FigureFigure 1. 1.Schematic Schematic illustrationillustration of the st stepseps involved involved in in SUMO SUMO-conjugation-conjugation and and de- de-conjugationconjugation processes.processes. SUMOylation SUMOylation starts starts with with the the action action of SUMO-specificof SUMO-specific proteases proteases (Ulp (Ulp/SENP/SENP family) family on) on newly synthesizednewly synthesized SUMO, whichSUMO, leads which to leads the generation to the generation of mature of mature SUMO SUMO with exposedwith exposed carboxyl-terminal carboxyl- GGterminal motif. TheGG motif. second The step second involves step SUMO-activating involves SUMO-activating enzyme (E1)-mediatedenzyme (E1)-mediated activation activation of the SUMO of proteinthe SUMO in an protein ATP-dependent in an ATP-dependent fashion, by fashion, first inducing by first inducing adenylation adenylation of the SUMO of the SUMO carboxyl-terminal, carboxyl- followedterminal, by followed the energy-rich by the energy thioester-rich bond thioester formation bond betweenformation the between thiol group the thiol of cysteine group of present cysteine in the catalyticpresent site in the of thecatalytic E1 enzyme site of the and E1 the enzyme C-terminal and the glycine C-terminal residue glycine of the residue SUMO of protein.the SUMO The protein. activated The activated SUMO is next transferred from the E1 enzyme to the cysteine residue present in the SUMO is next transferred from the E1 enzyme to the cysteine residue present in the catalytic site of the catalytic site of the SUMO-conjugating enzyme (E2), through the thioester linkage. With the help of SUMO-conjugating enzyme (E2), through the thioester linkage. With the help of the SUMO ligase (E3), the SUMO ligase (E3), SUMO is further transferred from the E2 enzyme to the target protein via SUMO is further transferred from the E2 enzyme to the target protein via isopeptide bond formation isopeptide bond formation between the C-terminal carboxyl group of SUMO and the ε-amino group between the C-terminal carboxyl group of SUMO and the "-amino group of the lysine residue in the of the lysine residue in the target protein. SUMO-specific proteases also cleave an isopeptide bond target protein. SUMO-specific proteases also cleave an isopeptide bond between SUMO and the target between SUMO and the target protein, resulting in the generation of an unSUMOylated target protein protein, resulting in the generation of an unSUMOylated target protein and free SUMO. and free SUMO. The acceptor lysine amino acids in SUMO target proteins are usually located within the consensus The acceptor lysine amino acids in SUMO target proteins are usually located within the motifconsensusYKxE, withmotifY ΨKxE,, K, x and with E representing Ψ, K, x and aE branched representing aliphatic a branched amino acidaliphatic residue, amino SUMO-conjugating acid residue, lysineSUMO residue,-conjugating any amino lysine acid residue, residue any and amino glutamic acid residue acid residue, and glutamic respectively acid [residue,2,3]. Specific respectively SUMO E3 ligases[2,3]. areSpecific involved SUMO in E3 the ligases SUMOylation are involved of cellular in the SUMOylation proteins [1–3 ].of SUMO cellular target proteins proteins [1–3]. haveSUMO been reportedtarget proteins in several ha cellve been organelles, reported including in several the cell nucleus, organelles endoplasmic, including reticulumthe nucleus, and endoplasmic mitochondria, thereticulum cytoplasm and and mitochondria, the plasma membranethe cytoplasm [2, 4and]. SUMOylation the plasma membrane could aff ect[2,4] di. ffSUMOylationerent aspects could of target proteins,affect different including aspects subcellular of target localization, proteins, including activity subcellular and stability, localization, blocking activity other and lysine-targeting stability, modificationsblocking other and lysine modulation-targeting of modifications protein–protein and interaction modulation [1 ,of2, 5protein]. The– SUMOprotein modification interaction [1,2,5] enzymes. and SUMO target proteins, and their effectors, contain a short SUMO interaction motif (SIM) which J. Fungi 2020, 6, 32 3 of 19 is pivotal to the relay of SUMOylation consequences [4,6,7]. The SUMO polypeptide also interacts non-covalently with SIM-containing proteins, and regulates their functions [1,3,4,7]. The deSUMOylase (SUMO-cleaving enzyme/isopeptidase) enzymes are pivotal to the maintenance of a cellular pool of readily available free SUMO, as these can release SUMO by cleaving SUMO-substrate bond from SUMOylated proteins, thereby making SUMOylation a dynamic and reversible post-translational modification [1,3,4,8]. Many internal and external cues, including cell cycle stage and thermal and oxidative
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