The Nucleolus as a Proteostasis Regulator

Amer-Sarsour, Fatima; Ashkenazi, Avraham

doi:10.1016/j.tcb.2019.08.002

Cited by 14 publications

(8 citation statements)

References 9 publications

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“…Studies in HEK293T cells transfected with artificial beta-sheet proteins, mimicking prefibrillar and fibrillar aggregate formation suggested that NPM1 might shield mHTT aggregate surface [ 57 ]. Our finding that the disruption of nucleolar integrity, and NPM1 release from the nucleolus, which promotes the loss of a diffuse mHTT state, reconciles with the role of nucleolar integrity in protein quality control and formation of protein aggregates [ 4 , 33 , 34 ].…”

Section: Discussionsupporting

confidence: 60%

Nucleolar stress controls mutant Huntington toxicity and monitors Huntington’s disease progression

et al. 2021

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Transcriptional and cellular-stress surveillance deficits are hallmarks of Huntington’s disease (HD), a fatal autosomal-dominant neurodegenerative disorder caused by a pathological expansion of CAG repeats in the Huntingtin (HTT) gene. The nucleolus, a dynamic nuclear biomolecular condensate and the site of ribosomal RNA (rRNA) transcription, is implicated in the cellular stress response and in protein quality control. While the exact pathomechanisms of HD are still unclear, the impact of nucleolar dysfunction on HD pathophysiology in vivo remains elusive. Here we identified aberrant maturation of rRNA and decreased translational rate in association with human mutant Huntingtin (mHTT) expression. The protein nucleophosmin 1 (NPM1), important for nucleolar integrity and rRNA maturation, loses its prominent nucleolar localization. Genetic disruption of nucleolar integrity in vulnerable striatal neurons of the R6/2 HD mouse model decreases the distribution of mHTT in a disperse state in the nucleus, exacerbating motor deficits. We confirmed NPM1 delocalization in the gradually progressing zQ175 knock-in HD mouse model: in the striatum at a presymptomatic stage and in the skeletal muscle at an early symptomatic stage. In Huntington’s patient skeletal muscle biopsies, we found a selective redistribution of NPM1, similar to that in the zQ175 model. Taken together, our study demonstrates that nucleolar integrity regulates the formation of mHTT inclusions in vivo, and identifies NPM1 as a novel, readily detectable peripheral histopathological marker of HD progression.

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Section: Discussionsupporting

confidence: 60%

Nucleolar stress controls mutant Huntington toxicity and monitors Huntington’s disease progression

et al. 2021

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“…Importantly, new data indicate that in addition to their crucial role in ribosome biogenesis nucleoli exert critical functions in protein quality control and proteostasis (Alberti and Carra, 2019;Amer-Sarsour and Ashkenazi, 2019;Mende and Muller, 2021). Similar to what was observed in PML NBs, aberrant translation products or misfolded proteins accumulate transiently in nucleoli for further clearance by the chaperone machinery (Frottin et al, 2019;Mediani et al, 2019b).…”

Section: Sumo Conjugation-deconjugation In the Nucleolusmentioning

confidence: 57%

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

Keiten-Schmitz

Röder

Hornstein

et al. 2021

Front. Mol. Biosci.

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Spatial organization of cellular processes in membranous or membrane-less organelles (MLOs, alias molecular condensates) is a key concept for compartmentalizing biochemical pathways. Prime examples of MLOs are the nucleolus, PML nuclear bodies, nuclear splicing speckles or cytosolic stress granules. They all represent distinct sub-cellular structures typically enriched in intrinsically disordered proteins and/or RNA and are formed in a process driven by liquid-liquid phase separation. Several MLOs are critically involved in proteostasis and their formation, disassembly and composition are highly sensitive to proteotoxic insults. Changes in the dynamics of MLOs are a major driver of cell dysfunction and disease. There is growing evidence that post-translational modifications are critically involved in controlling the dynamics and composition of MLOs and recent evidence supports an important role of the ubiquitin-like SUMO system in regulating both the assembly and disassembly of these structures. Here we will review our current understanding of SUMO function in MLO dynamics under both normal and pathological conditions.

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“…Figure1b, all these nuclear baits were located exclusively to the nucleus upon transient expression, although some appeared more concentrated in nucleoli or unspecific nuclear bodies, irrespective of the position of the H2B or the nature or position of the peptide tag (see pH2B_mCherry_SunTagv4, panels of A; pH2B_mCherry_HA, panels of C; pmCherry_ALFA_H2B, panels of H; pSunTagv4_mCherry_H2B, panels of I; pHA_mCherry_H2B, panels of K; pALFA_mCherry_H2B, panels of L; pmCherry_H2B, panels of M). The different localizations in the nucleus might be due to an accumulation in particular sub-nuclear structures for coping with the overexpression (Amer-Sarsour and Ashkenazi, 2019; Rekulapally and Suresh, 2019) or might reflect the different localization of the H2B fusion protein during the cell cycle phases (Duronio and Marzluff, 2017; Kurat et al, 2014; Romeo and Schumperli, 2016). Moreover, it could also reflect the rapid turnover of the histone H2B specifically in chromatin domains with high transcriptional activity (Kimura and Cook, 2001).…”

Section: Resultsmentioning

confidence: 99%

Protein manipulation using single copies of short peptide tags in cultured cells and inDrosophila melanogaster

Viganò

Ell

Kustermann

et al. 2020

Preprint

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Cellular development and specialized cellular functions are regulated processes which rely on highly dynamic molecular interactions among proteins, distributed in all cell compartments. Analysis of these interactions and their mechanisms of action has been one of the main topics in cellular and developmental research over the last fifty years.Studying and understanding the functions of proteins of interest (POIs) has been mostly achieved by their alteration at the genetic level and the analysis of the phenotypic changes generated by these alterations. Although genetic and reverse genetic technologies contributed to the vast majority of information and knowledge we have gathered so far, targeting specific interactions of POIs in a time-and spacecontrolled manner or analyzing the role of POIs in dynamic cellular processes such as cell migration or cell division would require more direct approaches. The recent development of specific protein binders, which can be expressed and function intracellularly, together with several improvements in synthetic biology techniques, have contributed to the creation of a new toolbox for direct protein manipulations. We selected a number of short tag epitopes for which protein binders from different scaffolds have been developed and tested whether these tags can be bound by the corresponding protein binders in living cells when they are inserted in a single copy in a POI. We indeed find that in all cases, a single copy of a short tag allows protein binding and manipulation. Using Drosophila, we also find that single short tags can be recognized and allow degradation and relocalization of POIs in vivo.

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The Nucleolus as a Proteostasis Regulator

Cited by 14 publications

References 9 publications

Nucleolar stress controls mutant Huntington toxicity and monitors Huntington’s disease progression

Nucleolar stress controls mutant Huntington toxicity and monitors Huntington’s disease progression

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

Protein manipulation using single copies of short peptide tags in cultured cells and inDrosophila melanogaster

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