Ubiquitination Regulates Expression of the Serine/Arginine-rich Splicing Factor 1 (SRSF1) in Normal and Systemic Lupus Erythematosus (SLE) T Cells

Moulton, Vaishali R.; Gillooly, Andrew R.; Tsokos, George C.

doi:10.1074/jbc.m113.518662

Cited by 42 publications

(28 citation statements)

References 39 publications

(39 reference statements)

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“…Such an observation was not anticipated but the proteasome is one of the many interconnected protein machinery, such as chromatin remodelers, transcription factors and the RNA polymerase, that together play important roles in regulatory processes (Komili and Silver, 2008). Our observation can also be related to previous studies that indicated an interconnection between 26S proteasome and the spliceosome machinery (Bellare et al, 2008;Bieler et al, 2012), including splicing factors such as SR proteins and hnRNPs (Koumbadinga et al, 2015;Moulton et al, 2014). To our knowledge, this is the first study highlighting modulation of IKBKAP mRNA alternative splicing and IKAP/hELP1 expression levels by proteasome inhibitors in FD pathology.…”

Section: Discussionsupporting

confidence: 60%

Proteasome inhibitors to alleviate aberrant IKBKAP mRNA splicing and low IKAP/hELP1 synthesis in familial dysautonomia

Hervé

Ibrahim

2017

Neurobiology of Disease

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FD is a rare neurodegenerative disorder caused by a mutation of the IKBKAP gene, which induces low expression levels of the Elongator subunit IKAP/hELP1 protein. A rational strategy for FD treatment could be to identify drugs increasing IKAP/hELP1 expression levels by blocking protein degradation pathways such as the 26S proteasome. Proteasome inhibitors are promising molecules emerging in cancer treatment and could thus constitute an enticing pharmaceutical strategy for FD treatment. Therefore, we tested three proteasome inhibitors on FD human olfactory ecto-mesenchymal stem cells (hOE-MSCs): two approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA), bortezomib and carfilzomib, as well as epoxomicin. Although all 3 inhibitors demonstrated activity in correcting IKBKAP mRNA aberrant splicing, carfilzomib was superior in enhancing IKAP/hELP1 quantity. Moreover, we observed a synergistic effect of suboptimal doses of carfilzomib on kinetin in improving IKBKAP isoforms ratio and IKAP/hELP1 expression levels allowing to counterbalance carfilzomib toxicity. Finally, we identified several dysregulated miRNAs after carfilzomib treatment that target proteasome-associated mRNAs and determined that IKAP/hELP1 deficiency in FD pathology is correlated to an overactivity of the 26S proteasome. Altogether, these results reinforce the rationale for using chemical compounds inhibiting the 26S proteasome as an innovative option for FD and a promising therapeutic pathway for many other neurodegenerative diseases.

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Section: Discussionsupporting

confidence: 60%

Proteasome inhibitors to alleviate aberrant IKBKAP mRNA splicing and low IKAP/hELP1 synthesis in familial dysautonomia

Hervé

Ibrahim

2017

Neurobiology of Disease

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“…However, more and more evidence indicate that this modification is also common to many other proteins of diverse functions in cells [14], including splicing factors [8]. Control of alternative splicing and/or splicing factors by protein degradation or ubiquitination has been observed as well [9][10][11]16,17]. Moreover, crosstalk between the acetylation and ubiquitination pathways controls important cellular proteins such as p53 through competition for the posttranslational modification of particular lysines (K Ac/Ub ) [18,19].…”

Section: Introductionmentioning

confidence: 96%

“…Of the protein modifications in cell signaling pathways, acetylation and ubiquitination each has recently been found to regulate splicing [8][9][10][11][12][13][14][15][16]. In these studies, acetylation/deacetylation effect on alternative splicing has been examined mostly from the point of histone modifications coupled with chromatin remodeling and transcription.…”

Section: Introductionmentioning

confidence: 99%

Increased stability of heterogeneous ribonucleoproteins by a deacetylase inhibitor

Koumbadinga

Mahmood

Lei

et al. 2015

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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“…At the protein level, increased ubiquitination and protein degradation of CD3ζ chain was observed in T cells from SLE patients [ 33 ]. Interestingly, SRSF1 undergoes ubiquitination and proteasome degradation during normal T cell activation, and exhibits increased ubiquitination in T cells from SLE patients compared with healthy individuals [ 34 ]. Our finding of a direct correlation between the protein expression of SRSF1 and CD3ζ in SLE T cells ( Fig 1 ) not only reflects the SRSF1 mediated regulation of CD3ζ , but also common regulatory mechanisms that may be dysregulated in SLE.…”

Section: Discussionmentioning

confidence: 99%

Serine Arginine-Rich Splicing Factor 1 (SRSF1) Contributes to the Transcriptional Activation of CD3ζ in Human T Cells

et al. 2015

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T lymphocytes from many patients with systemic lupus erythematosus (SLE) express decreased levels of the T cell receptor (TCR)-associated CD3 zeta (ζ) signaling chain, a feature directly linked to their abnormal phenotype and function. Reduced mRNA expression partly due to defective alternative splicing, contributes to the reduced expression of CD3ζ chain. We previously identified by oligonucleotide pulldown and mass spectrometry approaches, the serine arginine-rich splicing factor 1 (SRSF1) binding to the 3’ untranslated region (UTR) of CD3ζ mRNA. We showed that SRSF1 regulates alternative splicing of the 3’UTR of CD3ζ to promote expression of the normal full length 3`UTR over an unstable splice variant in human T cells. In this study we show that SRSF1 regulates transcriptional activation of CD3ζ. Specifically, overexpression and silencing of SRSF1 respectively increases and decreases CD3ζ total mRNA and protein expression in Jurkat and primary T cells. Using promoter-luciferase assays, we show that SRSF1 enhances transcriptional activity of the CD3ζ promoter in a dose dependent manner. Chromatin immunoprecipitation assays show that SRSF1 is recruited to the CD3ζ promoter. These results indicate that SRSF1 contributes to transcriptional activation of CD3ζ. Thus our study identifies a novel mechanism whereby SRSF1 regulates CD3ζ expression in human T cells and may contribute to the T cell defect in SLE.

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Ubiquitination Regulates Expression of the Serine/Arginine-rich Splicing Factor 1 (SRSF1) in Normal and Systemic Lupus Erythematosus (SLE) T Cells

Cited by 42 publications

References 39 publications

Proteasome inhibitors to alleviate aberrant IKBKAP mRNA splicing and low IKAP/hELP1 synthesis in familial dysautonomia

Proteasome inhibitors to alleviate aberrant IKBKAP mRNA splicing and low IKAP/hELP1 synthesis in familial dysautonomia

Increased stability of heterogeneous ribonucleoproteins by a deacetylase inhibitor

Serine Arginine-Rich Splicing Factor 1 (SRSF1) Contributes to the Transcriptional Activation of CD3ζ in Human T Cells

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