<scp>MG</scp>132‐induced progerin clearance is mediated by autophagy activation and splicing regulation

Harhouri, Karim; Navarro, Claire; Depetris, Danielle; Matteï, Marie‐Geneviève; Nissan, Xavier; Cau, Pierre; Sandre-Giovannoli, Annachiara De; Lévy, Nicolas

doi:10.15252/emmm.201607315

Cited by 109 publications

(98 citation statements)

References 85 publications

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“…Autophagy activation has been viewed as a compensatory protein degradation mechanism when proteasome function is inhibited [18, 39]. In agreement to this, our results also demonstrated that MG132 treatment significantly increased LC3II conversion along with accumulation of poly-ubiquitinated proteins in HEK293 cells transiently transfected with either vector control or myc-tagged EBNA3C (Fig.…”

Section: Resultssupporting

confidence: 89%

“…MG132 treatment was shown to enhance progerin clearance through autophagy and regulating splicing mechanisms by downregulating SRSF-1 [39]. Besides its proteolytic functions, proteasomal machinery also provides non-proteolytic activities engaging transcriptional and post-transcriptional regulation of multiple cellular genes [39,66,84]. In agreement to this, our RNA-seq data reveals that proteasomal inhibition enhances transcriptional activation of genes (viz.…”

Section: Discussionsupporting

confidence: 78%

“…Previously, proteasome inhibitors, such as MG132 have been demonstrated to exert substantial protective effect on cardiovascular and renal injury and appear to be potentially effective drugs in blocking oxidative damage as well as increased atherosclerosis in rabbits [80,81,82,83]. MG132 treatment was shown to enhance progerin clearance through autophagy and regulating splicing mechanisms by downregulating SRSF-1 [39]. Besides its proteolytic functions, proteasomal machinery also provides non-proteolytic activities engaging transcriptional and post-transcriptional regulation of multiple cellular genes [39,66,84].…”

Section: Discussionmentioning

confidence: 99%

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Proteasomal Inhibition Triggers Viral Oncoprotein Degradation via Autophagy-Lysosomal Pathway

Gain¹,

Malik²,

Bhattacharjee³

et al. 2019

Preprint

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26 Epstein-Barr virus (EBV) nuclear oncoprotein EBNA3C is essential for B-cell transformation 27 and development of several B-cell lymphomas particularly those are generated in an immuno-28 compromised background. EBNA3C recruits ubiquitin-proteasome machinery for deregulating 29 multiple cellular oncoproteins and tumor suppressor proteins. Although EBNA3C is found to be 30 ubiquitinated at its N-terminal region and interacts with 20S proteasome, the viral protein is 31 surprisingly stable in growing B-lymphocytes. EBNA3C can also circumvent autophagy-lysosomal 32 mediated protein degradation and subsequent antigen presentation for T-cell recognition. Recently, 33 we have shown that EBNA3C enhances autophagy, which serve as a prerequisite for B-cell survival 34 particularly under growth deprivation conditions. We now demonstrate that proteasomal inhibition 35 by MG132 induces EBNA3C degradation both in EBV transformed B-lymphocytes and ectopic-36 expression systems. Interestingly, MG132 treatment promotes degradation of two EBNA3 family 37 oncoproteins -EBNA3A and EBNA3C, but not the viral tumor suppressor protein EBNA3B. EBNA3C 38 degradation induced by proteasomal inhibition is partially blocked when autophagy-lysosomal 39 pathway is inhibited. In response to proteasomal inhibition, EBNA3C is predominantly K63-linked 40 polyubiquitinated, colocalized with the autophagy-lsyosomal fraction in the cytoplasm and 41 participated within p62-LC3B complex, which facilitates autophagy-mediated degradation. We 42 further show that the degradation signal is present at the first 50 residues of the N-terminal region 43 of EBNA3C. Proteasomal inhibition reduces the colony formation ability of this important viral 44 oncoprotein, increases transcriptional activation of both latent and lytic gene expression and 45 induces viral reactivation from EBV transformed B-lymphocytes. Altogether, this study offers 46 rationale to use proteasome inhibitors as potential therapeutic strategy against multiple EBV 47 associated B-cell lymphomas, where EBNA3C is expressed. 48 49 50 3 | P a g e 51 Author Summary 52 Epstein-Barr virus (EBV) establishes latent infection in B-lymphocytes and is associated with 53 a number of human malignancies, both of epithelial and lymphoid origin. EBV encoded EBNA3 54 family of nuclear latent antigens comprising of EBNA3A, EBNA3B, and EBNA3C are unique to 55 immunoblastic lymphomas. While EBNA3A and EBNA3C are involved in blocking many important 56 tumor suppressive mechanisms, EBNA3B exhibits tumor suppressive functions. Although EBNA3 57 proteins, in particular EBNA3C, interact with and employ different protein degradation machineries 58 to induce B-cell lymphomagenesis, these viral proteins are extremely stable in growing B-59 lymphocytes. To this end, we now demonstrate that proteasomal inhibition leads to specifically 60 degradation of oncogenic EBNA3A and EBNA3C proteins, whereas EBNA3B remains unaffected. 61 Upon proteasomal inhibition, EBNA3C degradation occurs via autophagy-lysosomal pathway, 62 thro...

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Section: Resultssupporting

confidence: 89%

Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Proteasomal Inhibition Triggers Viral Oncoprotein Degradation via Autophagy-Lysosomal Pathway

Gain¹,

Malik²,

Bhattacharjee³

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Lamins are type V intermediate filament proteins that form the nuclear lamina, a filamentous network underlying the inner nuclear membrane of eukaryotic cells . Mutation, aberrant splicing and abnormal expression of lamin A/C, the nuclear A‐type lamins, will lead to the disruption of various crucial cellular functions and result in a number of devastating diseases. For example, in the cardiovascular system, mutation of lamin A/C caused by Lmna mutations participates in up to 10% of dilated cardiomyopathies (DCMs) and underlies a spectrum of other diseases including muscular dystrophy, lipodystrophy and acrogeria syndromes .…”

Section: Discussionmentioning

confidence: 99%

Lamin A/C negatively regulated by miR‐124‐3p modulates apoptosis of vascular smooth muscle cells during cyclic stretch application in rats

Bao

Shi

et al. 2019

Acta Physiologica

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Aim Apoptosis of vascular smooth muscle cells (VSMCs) influenced by abnormal cyclic stretch is crucial for vascular remodelling during hypertension. Lamin A/C, a nuclear envelope protein, is mechano‐responsive, but the role of lamin A/C in VSMC apoptosis is still unclear. Methods FX‐5000T Strain Unit provided cyclic stretch (CS) in vitro. AnnexinV/PI and cleaved Caspase 3 ELISA detected apoptosis. qPCR was used to investigate the expression of miR‐124‐3p and a luciferase reporter assay was used to evaluate the ability of miR‐124‐3p binding to the Lmna 3’UTR. Protein changes of lamin A/C and relevant molecules were detected using western blot. Ingenuity Pathway Analysis and Protein/DNA array detected the potential transcription factors. Renal hypertensive rats verified these changes. Results High cyclic stretch (15%‐CS) induced VSMC apoptosis and repressed lamin A/C expressions compared with normal (5%‐CS) control. Downregulation of lamin A/C enhanced VSMC apoptosis. In addition, 15%‐CS had no significant effect on mRNA expression of Lmna, and lamin A/C degradation was not induced by autophagy. 15%‐CS elevated miR‐124‐3p bound to the 3’UTR of Lmna and negatively regulated protein expression of lamin A/C. Similar changes occurred in renal hypertensive rats compared with sham controls. Lamin A/C repression affected activity of TP53, CREB1, MYC, STAT1/5/6 and JUN, which may in turn affect apoptosis. Conclusion Our data suggested that the decreased expression of lamin A/C upon abnormal cyclic stretch and hypertension may induce VSMC apoptosis. These mechano‐responsive factors play important roles in VSMC apoptosis and might be novel therapeutic targets for vascular remodelling in hypertension.

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“…Nuclear defects in HGPS cells can be largely alleviated by farnesyltransferase inhibitors (FTIs) (Capell et al, 2005; Hamczyk et al, 2018; Toth et al, 2005). However, disruption to other nuclear compartments, such as nuclear bodies, in HGPS is rarely reported (Harhouri et al, 2017). A recent study identified disordered structures of PML NB in late passage of cultured HGPS cells (Harhouri et al, 2017); this study, however, did not clarify their function or effects on cellular processes.…”

Section: Introductionmentioning

confidence: 99%

PML2‐mediated thread‐like nuclear bodies mark late senescence in Hutchinson–Gilford progeria syndrome

Wang

Qian

et al. 2020

Aging Cell

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Progerin accumulation disrupts nuclear lamina integrity and causes nuclear structure abnormalities, leading to premature aging, that is, Hutchinson–Gilford progeria syndrome (HGPS). The roles of nuclear subcompartments, such as PML nuclear bodies (PML NBs), in HGPS pathogenesis, are unclear. Here, we show that classical dot‐like PML NBs are reorganized into thread‐like structures in HGPS patient fibroblasts and their presence is associated with late stage of senescence. By co‐immunoprecipitation analysis, we show that farnesylated Progerin interacts with human PML2, which accounts for the formation of thread‐like PML NBs. Specifically, human PML2 but not PML1 overexpression in HGPS cells promotes PML thread development and accelerates senescence. Further immunofluorescence microscopy, immuno‐TRAP, and deep sequencing data suggest that these irregular PML NBs might promote senescence by perturbing NB‐associated DNA repair and gene expression in HGPS cells. These data identify irregular structures of PML NBs in senescent HGPS cells and support that the thread‐like PML NBs might be a novel, morphological, and functional biomarker of late senescence.

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MG132‐induced progerin clearance is mediated by autophagy activation and splicing regulation

Cited by 109 publications

References 85 publications

Proteasomal Inhibition Triggers Viral Oncoprotein Degradation via Autophagy-Lysosomal Pathway

Proteasomal Inhibition Triggers Viral Oncoprotein Degradation via Autophagy-Lysosomal Pathway

Lamin A/C negatively regulated by miR‐124‐3p modulates apoptosis of vascular smooth muscle cells during cyclic stretch application in rats

PML2‐mediated thread‐like nuclear bodies mark late senescence in Hutchinson–Gilford progeria syndrome

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