SUMO: Glue or Solvent for Phase-Separated Ribonucleoprotein Complexes and Molecular Condensates?

Keiten-Schmitz, Jan; Röder, Linda; Hornstein, Eran; Müller-McNicoll, Michaela; Müller, Stefan

doi:10.3389/fmolb.2021.673038

Cited by 48 publications

(51 citation statements)

References 91 publications

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“…The role of SUMO/SIM interactions in PML-NB formation may be but one example of a broader role of these interactions in the formation of phase-separated membraneless organelles. For example, these interactions could drive or regulate the formation and/or dynamics of nuclear speckles, which are phase-separated ribonucleoprotein aggregates with essential roles in RNA processing [ 44 ]. In addition, the Polycomb bodies found in many metazoan cell types are enriched for SUMO [ 45 ].…”

Section: Role For Sumo/sim Interactions In Structure and Function Of Pml Bodies And Other Phase Separated Organellesmentioning

confidence: 99%

SUMO Interacting Motifs: Structure and Function

Yau

Sander

Eidson

et al. 2021

Cells

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Small ubiquitin-related modifier (SUMO) is a member of the ubiquitin-related protein family. SUMO modulates protein function through covalent conjugation to lysine residues in a large number of proteins. Once covalently conjugated to a protein, SUMO often regulates that protein’s function by recruiting other cellular proteins. Recruitment frequently involves a non-covalent interaction between SUMO and a SUMO-interacting motif (SIM) in the interacting protein. SIMs generally consist of a four-residue-long hydrophobic stretch of amino acids with aliphatic non-polar side chains flanked on one side by negatively charged amino acid residues. The SIM assumes an extended β-strand-like conformation and binds to a conserved hydrophobic groove in SUMO. In addition to hydrophobic interactions between the SIM non-polar core and hydrophobic residues in the groove, the negatively charged residues in the SIM make favorable electrostatic contacts with positively charged residues in and around the groove. The SIM/SUMO interaction can be regulated by the phosphorylation of residues adjacent to the SIM hydrophobic core, which provide additional negative charges for favorable electrostatic interaction with SUMO. The SUMO interactome consists of hundreds or perhaps thousands of SIM-containing proteins, but we do not fully understand how each SUMOylated protein selects the set of SIM-containing proteins appropriate to its function. SIM/SUMO interactions have critical functions in a large number of essential cellular processes including the formation of membraneless organelles by liquid–liquid phase separation, epigenetic regulation of transcription through histone modification, DNA repair, and a variety of host–pathogen interactions.

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Section: Role For Sumo/sim Interactions In Structure and Function Of Pml Bodies And Other Phase Separated Organellesmentioning

confidence: 99%

SUMO Interacting Motifs: Structure and Function

Yau

Sander

Eidson

et al. 2021

Cells

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“…Indeed, RNF4 silencing or proteasome inhibition can both result in the accumulation of cellular SUMO2/3 conjugates, implying that the latter are routinely destined for basal RNF4-induced ubiquitylation and proteasomal targeting [ 52 , 78 , 79 ]. Recent findings have also linked STUbL to the elimination of stress granules in the cytoplasm [ 40 ]. These membrane-less organelles are formed by co-accumulation of mRNAs and RNA-binding proteins under proteotoxic stress, such as heat shock or oxidation.…”

Section: Sumo In Stressmentioning

confidence: 99%

“…These membrane-less organelles are formed by co-accumulation of mRNAs and RNA-binding proteins under proteotoxic stress, such as heat shock or oxidation. Recent evidence indicates that multiple SUMO/SIM interactions may facilitate the assembly and maintenance of stress granules [ 40 ].…”

Section: Sumo In Stressmentioning

confidence: 99%

“…These sites include several membranes-less organelles, such as stress granules and nuclear bodies (in particular, PML nuclear bodies, which will be further discussed in the stress section), the nucleolus and the telomeric regions [ 3 , 37 ]. Reciprocally, sumoylation may promote co-segregation of functionally unrelated proteins from the nucleoplasm to form topologically distinct droplets, a process unraveled by in vitro liquid-liquid phase separation experiments [ 40 , 41 ].…”

Section: Introductionmentioning

confidence: 99%

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Sumoylation in Physiology, Pathology and Therapy

Şahin

Thé

Lallemand-Breitenbach

2022

Cells

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Sumoylation is an essential post-translational modification that has evolved to regulate intricate networks within emerging complexities of eukaryotic cells. Thousands of target substrates are modified by SUMO peptides, leading to changes in protein function, stability or localization, often by modulating interactions. At the cellular level, sumoylation functions as a key regulator of transcription, nuclear integrity, proliferation, senescence, lineage commitment and stemness. A growing number of prokaryotic and viral proteins are also emerging as prime sumoylation targets, highlighting the role of this modification during infection and in immune processes. Sumoylation also oversees epigenetic processes. Accordingly, at the physiological level, it acts as a crucial regulator of development. Yet, perhaps the most prominent function of sumoylation, from mammals to plants, is its role in orchestrating organismal responses to environmental stresses ranging from hypoxia to nutrient stress. Consequently, a growing list of pathological conditions, including cancer and neurodegeneration, have now been unambiguously associated with either aberrant sumoylation of specific proteins and/or dysregulated global cellular sumoylation. Therapeutic enforcement of sumoylation can also accomplish remarkable clinical responses in various diseases, notably acute promyelocytic leukemia (APL). In this review, we will discuss how this modification is emerging as a novel drug target, highlighting from the perspective of translational medicine, its potential and limitations.

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“…Embryos of mice bred without the SUMO-conjugating enzyme E2 did not survive beyond the early postimplantation stage [ 889 ]. The interplay between ubiquitin and SUMO in the nucleolar compartment may be driven by LLPS [ 890 , 891 ], because the inhibition of ubiquitination leads to an accumulation of SUMOylated proteins that condense into MLOs known as promyelocytic leukemia proteins (PMLs) in nucleoli [ 867 , 892 ].…”

Section: Melatonin May Attenuate the Stress-induced Aggregation Of Pathological Mlos Via Post-translational Modification And Rna Modificamentioning

confidence: 99%

Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

Loh¹,

Reíter

2021

Antioxidants

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Biomolecular condensates are membraneless organelles (MLOs) that form dynamic, chemically distinct subcellular compartments organizing macromolecules such as proteins, RNA, and DNA in unicellular prokaryotic bacteria and complex eukaryotic cells. Separated from surrounding environments, MLOs in the nucleoplasm, cytoplasm, and mitochondria assemble by liquid–liquid phase separation (LLPS) into transient, non-static, liquid-like droplets that regulate essential molecular functions. LLPS is primarily controlled by post-translational modifications (PTMs) that fine-tune the balance between attractive and repulsive charge states and/or binding motifs of proteins. Aberrant phase separation due to dysregulated membrane lipid rafts and/or PTMs, as well as the absence of adequate hydrotropic small molecules such as ATP, or the presence of specific RNA proteins can cause pathological protein aggregation in neurodegenerative disorders. Melatonin may exert a dominant influence over phase separation in biomolecular condensates by optimizing membrane and MLO interdependent reactions through stabilizing lipid raft domains, reducing line tension, and maintaining negative membrane curvature and fluidity. As a potent antioxidant, melatonin protects cardiolipin and other membrane lipids from peroxidation cascades, supporting protein trafficking, signaling, ion channel activities, and ATPase functionality during condensate coacervation or dissolution. Melatonin may even control condensate LLPS through PTM and balance mRNA- and RNA-binding protein composition by regulating N6-methyladenosine (m6A) modifications. There is currently a lack of pharmaceuticals targeting neurodegenerative disorders via the regulation of phase separation. The potential of melatonin in the modulation of biomolecular condensate in the attenuation of aberrant condensate aggregation in neurodegenerative disorders is discussed in this review.

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SUMO: Glue or Solvent for Phase-Separated Ribonucleoprotein Complexes and Molecular Condensates?

Cited by 48 publications

References 91 publications

SUMO Interacting Motifs: Structure and Function

SUMO Interacting Motifs: Structure and Function

Sumoylation in Physiology, Pathology and Therapy

Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

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