Mutations in SKI in Shprintzen-Goldberg syndrome lead to attenuated TGF-β responses through SKI stabilization

Gori, Ilaria; George, Roger; Purkiss, A.; Strohbuecker, Stephanie; Randall, Rebecca A.; Ogrodowicz, R.W.; Carmignac, Virginie; Faivre, Laurence; Joshi, Dhira; Kjær, Svend; Hill, Caroline S.

doi:10.1101/2020.10.07.330407

Cited by 2 publications

(2 citation statements)

References 84 publications

(110 reference statements)

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“…Intriguingly, the lysine 343 is located in the SAND domain of SKIL known to interact with SMAD4 ( 28 ) and RNF111 ( 5 ). It has been shown recently that besides its interaction with phospho-SMAD2/3 ( 4 ), interaction of SKIL with SMAD4 is also absolutely required for SKIL degradation ( 32 ). Altogether, these findings point out that RNF111 ubiquitylation of SKIL might occur at the interface of a SKIL–SMAD4–phospho-SMAD2/3 heteromeric complex, and future investigation in this direction would be critical to unravel the molecular mechanism of RNF111-dependent SKIL degradation in response to TGF-β.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Ubiquitylome Analysis Reveals the Specificity of RNF111/Arkadia E3 Ubiquitin Ligase for its Degradative Substrates SKI and SKIL/SnoN in TGF-β Signaling Pathway

Laigle¹,

Dingli²,

Amhaz³

et al. 2021

Molecular & Cellular Proteomics

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RNF111/Arkadia is an E3 ubiquitin ligase that activates the transforming growth factor-β (TGF-β) pathway by degrading transcriptional repressors SKIL/SnoN and SKI. Truncations of the RING C-terminal domain of RNF111 that abolish its E3 function and subsequently activate TGF-β signaling are observed in some cancers. In the present study, we sought to perform a comprehensive analysis of RNF111 endogenous substrates upon TGF-β signaling activation using an integrative proteomic approach. In that aim, we carried out label-free quantitative proteomics after the enrichment of ubiquitylated proteins (ubiquitylome) in parental U2OS cell line compared with U2OS CRISPR engineered clones expressing a truncated form of RNF111 devoid of its C-terminal RING domain. We compared two methods of enrichment for ubiquitylated proteins before proteomics analysis by mass spectrometry, the diGlycine (diGly) remnant peptide immunoprecipitation with a K-ε-GG antibody, and a novel approach using protein immunoprecipitation with a ubiquitin pan nanobody that recognizes all ubiquitin chains and monoubiquitylation. Although we detected SKIL ubiquitylation among 108 potential RNF111 substrates with the diGly method, we found that the ubiquitin pan nanobody method also constitutes a powerful approach because it enabled the detection of 52 potential RNF111 substrates including SKI, SKIL, and RNF111. Integrative comparison of the RNF111-dependent proteome and ubiquitylomes enabled the identification of SKI and SKIL as the only targets ubiquitylated and degraded by RNF111 E3 ligase function in the presence of TGF-β. Our results indicate that lysine 343 localized in the SAND domain of SKIL constitutes a target for RNF111 ubiquitylation and demonstrate that RNF111 E3 ubiquitin ligase function specifically targets SKI and SKIL ubiquitylation and degradation upon TGF-β pathway activation.

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Section: Discussionmentioning

confidence: 99%

Quantitative Ubiquitylome Analysis Reveals the Specificity of RNF111/Arkadia E3 Ubiquitin Ligase for its Degradative Substrates SKI and SKIL/SnoN in TGF-β Signaling Pathway

Laigle¹,

Dingli²,

Amhaz³

et al. 2021

Molecular & Cellular Proteomics

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“…Additionally, Shprintzen–Goldberg syndrome (SGS) is caused by mutations in the SKI gene proposed to interfere with SKI’s ability to bind and inactivate the transcriptional activity of Smad proteins [ 149 , 211 , 212 , 326 ]. More recently, however, these mutations have been shown to stabilize the SKI protein, causing attenuation rather than enhancement of TGF-β signaling as originally proposed [ 327 ].…”

Section: Genes Associated With Syndromic and Non-syndromic Hereditmentioning

confidence: 99%

Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies

Creamer

Bramel

MacFarlane

2021

Genes

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Thoracic aortic aneurysms (TAA) are permanent and localized dilations of the aorta that predispose patients to a life-threatening risk of aortic dissection or rupture. The identification of pathogenic variants that cause hereditary forms of TAA has delineated fundamental molecular processes required to maintain aortic homeostasis. Vascular smooth muscle cells (VSMCs) elaborate and remodel the extracellular matrix (ECM) in response to mechanical and biochemical cues from their environment. Causal variants for hereditary forms of aneurysm compromise the function of gene products involved in the transmission or interpretation of these signals, initiating processes that eventually lead to degeneration and mechanical failure of the vessel. These include mutations that interfere with transduction of stimuli from the matrix to the actin–myosin cytoskeleton through integrins, and those that impair signaling pathways activated by transforming growth factor-β (TGF-β). In this review, we summarize the features of the healthy aortic wall, the major pathways involved in the modulation of VSMC phenotypes, and the basic molecular functions impaired by TAA-associated mutations. We also discuss how the heterogeneity and balance of adaptive and maladaptive responses to the initial genetic insult might contribute to disease.

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Mutations in SKI in Shprintzen-Goldberg syndrome lead to attenuated TGF-β responses through SKI stabilization

Cited by 2 publications

References 84 publications

Quantitative Ubiquitylome Analysis Reveals the Specificity of RNF111/Arkadia E3 Ubiquitin Ligase for its Degradative Substrates SKI and SKIL/SnoN in TGF-β Signaling Pathway

Quantitative Ubiquitylome Analysis Reveals the Specificity of RNF111/Arkadia E3 Ubiquitin Ligase for its Degradative Substrates SKI and SKIL/SnoN in TGF-β Signaling Pathway

Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies

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