Sumoylation by Ubc9 Regulates the Stem Cell Compartment and Structure and Function of the Intestinal Epithelium in Mice

Demarque, Maud; Nacerddine, Karim; Neyret‐Kahn, Hélène; Andrieux, Alexandra; Danenberg, Esther; Jouvion, Grégory; Bomme, Perrine; Hamard, Ghislaine; Romagnolo, Béatrice; Terris, Benoı̂t; Cumano, Ana; Barker, Nick; Clevers, Hans; Dejean, Anne

doi:10.1053/j.gastro.2010.10.002

Cited by 57 publications

(77 citation statements)

References 32 publications

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“…Apart from virus infection, there is circumstantial evidence that IFN control over SUMO or PML abundance may be also important for other processes. Early progenitors are very SUMO rich, consistent with studies that have linked SUMOs to stem cell maintenance [48][49][50] . PML was also implicated in regulation of stem cell fate 51 , notably through TR2 sumoylation, which directly controls expression of Oct-4 (refs 52,53), or through p53 activation 54 .…”

Section: Discussionsupporting

confidence: 87%

Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication

Şahin¹,

Ferhi²,

Carnec³

et al. 2014

Nat Commun

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Small ubiquitin-related modifier (SUMO) protein conjugation onto target proteins regulates multiple cellular functions, including defence against pathogens, stemness and senescence. SUMO1 peptides are limiting in quantity and are thus mainly conjugated to high-affinity targets. Conjugation of SUMO2/3 paralogues is primarily stress inducible and may initiate target degradation. Here we demonstrate that the expression of SUMO1/2/3 is dramatically enhanced by interferons through an miRNA-based mechanism involving the Lin28/let-7 axis, a master regulator of stemness. Normal haematopoietic progenitors indeed display much higher SUMO contents than their differentiated progeny. Critically, SUMOs contribute to the antiviral effects of interferons against HSV1 or HIV. Promyelocytic leukemia (PML) nuclear bodies are interferon-induced domains, which facilitate sumoylation of a subset of targets. Our findings thus identify an integrated interferon-responsive PML/SUMO pathway that impedes viral replication by enhancing SUMO conjugation and possibly also modifying the repertoire of targets. Interferon-enhanced post-translational modifications may be essential for senescence or stem cell self-renewal, and initiate SUMO-dependent proteolysis.

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Section: Discussionsupporting

confidence: 87%

Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication

Şahin¹,

Ferhi²,

Carnec³

et al. 2014

Nat Commun

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“…Previous studies in yeast, drosophila, zebrafish, and mouse showed that global inhibition of SUMOylation at the organismal level selectively affects mitotic cells, resulting in cell cycle arrest, chromosome defect, nuclear structure disintegration, or even apoptosis in highly proliferative cells (18,19,(44)(45)(46)(47). In this study, nondividing status of most DP thymocytes (∼90%) (48) allowed us to interrogate the definitive role of SUMOylation pathway during T cell development, making it unnecessary to consider the interference from general defects incurred by Ubc9 deletion as in dividing cells.…”

Section: Discussionmentioning

confidence: 99%

“…Mice with Ubc9 fl/fl allele have been described previously (18). Primer 23 (59-AAG CTG TAG CAG GGA TGT GCT CTG G-39) and primer 24 (59-TTG ACA AGG CCC TTA GGT GAA CAC CTC TC-39) were used to distinguish wild-type (WT) Ubc9 (480 bp) from floxed Ubc9 allele (535 bp), whereas primer 22 (59-CAG CAG ATG GGG ATG AGT AAG-39) and primer 23 were used to confirm null allele (320 bp).…”

Section: Mice and Reagentsmentioning

confidence: 99%

“…Deletion of Ubc9 results in embryonic lethality in mice (18,19). To investigate the role of Ubc9-mediated SUMOylation in T cells, we crossed mice bearing an Ubc9 conditional allele (18) with the Cd4Cre strain, in which Cre expression is initiated at the DP stage of T cells (20).…”

Section: Disruption Of the Ubc9 Gene In T Cellsmentioning

confidence: 99%

“…To investigate the role of Ubc9-mediated SUMOylation in T cells, we crossed mice bearing an Ubc9 conditional allele (18) with the Cd4Cre strain, in which Cre expression is initiated at the DP stage of T cells (20). To investigate the deletion efficiency of Ubc9 gene, we sorted by FACS DP or SP thymocytes from Cd4Cre transgenic mice with WT or floxed (KO) Ubc9 allele.…”

Section: Disruption Of the Ubc9 Gene In T Cellsmentioning

confidence: 99%

See 2 more Smart Citations

Ubc9 Is Required for Positive Selection and Late-Stage Maturation of Thymocytes

Wang

Ding

Demarque

et al. 2017

The Journal of Immunology

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SUMOylation is an important posttranslational modification that regulates protein function in diverse biological processes. However, its role in early T cell development has not been genetically studied. UBC9 is the only E2 enzyme for all SUMOylation. In this study, by selectively deleting Ubc9 gene in T cells, we have investigated the functional roles of SUMOylation in T cell development. Loss of Ubc9 results in a significant reduction of CD4 and CD8 single-positive lymphocytes in both thymus and periphery. Ubc9-deficient cells exhibit defective late-stage maturation post the initial positive selection with increased apoptosis and impaired proliferation, among which attenuated IL-7 signaling was correlated with the decreased survival of Ubc9-deficent CD8 single-positive cells. Furthermore, NFAT nuclear retention induced by TCR signals was regulated by SUMOylation during thymocytes development. Our study thus reveals a novel posttranslational mechanism underlying T cell development.

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Spatiotemporal distribution of SUMOylation components during mouse brain development

Hasegawa

Yoshida

Nakamura

et al. 2014

J of Comparative Neurology

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Posttranslational modification of proteins might play an important role in brain cellular dynamics via the rapid turnover or functional change of critical proteins controlling neuronal differentiation or synaptic transmission. Small ubiquitin-like modifier protein (SUMO) is a family of ubiquitin-like small proteins that are covalently attached to target proteins to modify their function posttranslationally. Many cellular processes, such as transcription and protein trafficking, are regulated by SUMOylation, but its functional significance in the brain remains unclear. Although developmental regulation of SUMOylation levels in rat brain was recently demonstrated, no comparative immunohistochemical analysis of the cellular distribution profiles of SUMOylation components, including SUMO1, SUMO2/3, and Ubc9, has been undertaken so far. The present study used immunohistochemical and immunoblot analysis with the different developmental stages of mice and demonstrated the developmentally regulated distribution of SUMO1, SUMO2/3, and Ubc9 in the brain. During embryonic development, SUMOylation by SUMO1 and SUMO2/3 occurred in the nucleoplasm of nestin-positive neural stem cells. Although the total amount of SUMO-modified proteins decreased during postnatal brain development, intense and persistent accumulation of SUMO2/3 was detected throughout life in neural progenitor populations in neurogenic regions, including the subventricular zone and the hippocampal subgranular zone. In contrast, many neurons in the adult brain accumulated SUMO1 rather than SUMO2/3. Heavy immunoreactivity of SUMO1 was found in large projection neurons in the brainstem, whereas SUMO2/3 was almost absent from these areas. This heterogeneous distribution implies that both proteins play a specific and unique role in the brain.

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Sumoylation by Ubc9 Regulates the Stem Cell Compartment and Structure and Function of the Intestinal Epithelium in Mice

Cited by 57 publications

References 32 publications

Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication

Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication

Ubc9 Is Required for Positive Selection and Late-Stage Maturation of Thymocytes

Spatiotemporal distribution of SUMOylation components during mouse brain development

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