Insight into the world of ubiquitin has expanded considerably over the past decade and ubiquitin conjugation to proteins is known to be involved in controlling major biological processes. Our main goal is to better understand ubiquitylation/deubiquitylation events in health and disease to identify novel biomarkers and therapeutic targets for precision medicine.
Ubiquitylation is a rapid, reversible and versatile post-translational modification, directing proteins to a myriad of fates. A key regulatory step of the ubiquitylation cascade is dictated by the E3 ubiquitin ligase which confers substrate selectivity. The reversibility of this post-translational modification is driven by deubiquitinating enzymes responsible for removing ubiquitin conjugates from substrates. While best known for targeting proteins to proteasomal degradation, ubiquitylation is also used for proteolytic-independent functions. Of note, alteration of the ubiquitin pathway results in human disease pathogenesis including cancer, muscle disorders or inflammatory and infectious diseases. Importantly, components of the ubiquitin system are amenable to pharmacological manipulation.
A main objective of our team is to decipher the roles of the ASB2 E3 ubiquitin ligases in physiological and pathological settings using state-of-the-art mouse mutant models as well as cellular and molecular approaches. The ASB2 gene was initially identified by our group as a retinoic acid-responsive gene deregulated by the PML-RARα oncogenic protein in leukemia cells. ASB2 encodes two protein isoforms, ASB2α and ASB2β, that are the specificity subunits of Cullin 5-RING E3 ubiquitin ligases suggesting that ASB2 proteins exert their effects through the targeting of specific substrates for degradation by the proteasome. Investigating ASB2-ASB2 substrate axes will provide important mechanistic insights into the contribution of the ubiquitin pathway to major biological functions that could be exploited in therapeutic purposes.
The E3 ubiquitin ligase Asb2α in T helper 2 cells negatively regulates antitumor immunity in colorectal cancer.
Camille A. Spinner, Isabelle Lamsoul*, Arnaud Métais, Chanaëlle Febrissy, Christel Moog-Lutz and Pierre G. Lutz*
Cancer Immunology Research Published ahead of print June 7, 2019
Read the press release (in french)
Novelty and Significance: Understanding the molecular events that account for CD4+ effector T cell properties will shed light on cancer etiology and therapeutics. The escape of cancer cells from host immunosurveillance involves a shift in immune responses, including an imbalance in T helper 1 (Th1) and Th2 cells. A Th1-dominated immune response predicts positive outcome in colorectal cancer (CRC). Here, we reveal an unexpected role of ASB2α expressed in Th2 cells in the immune response to solid tumors. We found that high ASB2 levels associated with poor outcome in CRC and that loss of ASB2 attenuated colitis-associated tumorigenesis in mice. ASB2α repressed antitumor responses in a mouse model of colitis-associated tumorigenesis. Without it, Th2 cells had blunted cytokine production and antitumor immunity was enhanced. Taken together, our results substantiate a pro-tumor activity of Th2 cells in CRC and suggest that ASB2α may serve more broadly as a therapeutic target for malignancies driven by Th2 immune responses.
Our research topics
- Spinner CA et al. (2019) The E3 ubiquitin ligase Asb2α in T helper 2 cells negatively regulates antitumor immunity in colorectal cancer. Cancer Immunol Res, doi: 10.1158/2326-6066.CIR-18-0562
- Métais A et al. (2018) Asb2α-Filamin A axis is essential for cytoskeletal remodeling during heart development. Circulation Research 122:e34.
- Lamsoul I et al. (2013) ASB2α regulates migration of immature dendritic cells. Blood 122: 533-541
- Bello NF et al. (2009) The E3 ubiquitin ligase specificity subunit ASB2β is a novel regulator of muscle differentiation that targets filamin B to proteasomal degradation. Cell Death & Differentiation 16: 921-932
- Heuzé ML et al. (2008) ASB2 targets filamins A and B to proteasomal degradation. Blood 112: 5130-5140
From heart function to immune responses
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CNRS Research director in cell biology
CNRS Senior Research Associate in molecular and cellular biology
Professor in Cell Biology - University of Toulouse
Manuel S. Rodriguez
CNRS Senior Research Associate in molecular biology
Rosa Lopez Reyes
Fellow of the CONACYT
This is short list of our main publications.
Download a complete list of the papers of the team.
Download the complete list of the P.G. Lutz.
- Spinner CA et al. (2019) The E3 ubiquitin ligase Asb2α in T helper 2 cells negatively regulates antitumor immunity in colorectal cancer. Cancer Immunology Research, doi: 10.1158/2326-6066.CIR-18-0562.
- Métais A et al. (2018) Asb2α-Filamin A axis is essential for cytoskeletal remodeling during heart development. Circulation Research 122: e34.
- Thottakara T et al. (2015) The E3 ubiquitin ligase Asb2β is downregulated in a mouse model of hypertrophic cardiomyopathy and targets desmin for proteasomal degradation. Journal of Molecular and Cellular Cardiology 87: 214-224.
- Spinner CA et al. (2015) Substrates of the ASB2α E3 ubiquitin ligase in dendritic cells. Scientific Reports 5: 16269.
- Lamsoul I et al. (2013) ASB2α regulates migration of immature dendritic cells. Blood 122: 533-541.
- Razinia Z et al. (2011) The E3 ubiquitin ligase specificity subunit ASB2α targets filamins for proteasomal degradation by interacting with the filamin actin-binding domain. Journal of Cell Science 124: 2631-2641.
- Lamsoul I et al. (2011) Functional and structural insights into ASB2α, a novel regulator of integrin-dependent adhesion of hematopoietic cells. The Journal of Biological Chemistry 286: 30571-30581.
- Burande CF et al. (2009) A label-free quantitative proteomic strategy to identify E3 ubiquitin ligase substrates targeted to proteasome degradation. Molecular & Cellular Proteomics 8: 1719-1727.
- Bello NF et al. (2009) The E3 ubiquitin ligase specificity subunit ASB2β is a novel regulator of muscle differentiation that targets filamin B to proteasomal degradation. Cell Death and Differentiation 16: 921-932.
- Luissint AC et al. (2008) JAM-L mediated leukocyte adhesion to endothelial cells is regulated in cis by α4β1 integrin activation. The Journal of Cell Biology 183: 1159-1173.
- Heuzé ML et al. (2008) ASB2 targets filamins A and B to proteasomal degradation. Blood 112: 5130-5140.
- Heuzé ML et al. (2005) ASB2 is an elongin BC-interacting protein that can assemble with cullin 5 and rbx1 to reconstitute an E3 ubiquitin ligase complex. The Journal of Biological Chemistry 280: 5468-5474.
- Moog-Lutz C et al. (2003) JAML, a novel protein with characteristics of a Junctional Adhesion Molecule, is induced during differentiation of myeloid leukemia cells. Blood 102: 3371-3378.
- Lutz PG et al. (2002) Signaling revisited in acute promyelocytic leukemia. Leukemia 16: 1933-1939.
- Guibal FC et al. (2002) ASB2 inhibits growth and promotes commitment in myeloid leukemia cells. The Journal of Biological Chemistry 277: 218-224.
• David A Calderwood, Yale University, New Haven, USA
• Lucie Carrier, Institute of Experimental and Clinical Pharmacology, Hamburg, Germany
• Joan W & Ronald C Conaway, Stowers Institute, Kansas city, USA
• Ibrahim J Domian, Harvard Medical School, Cardiovascular Research Center, Boston, USA
• Delphine Duprez,, Institut de Biologie Paris-Seine, Paris
• Ana-Maria Lennon-Dumenil, Institut Curie, Paris
• Isabelle Maridonneau-Parini & Renaud Poincloux, IPBS, Toulouse
• Michel Nussenzweig, Howard Hughes Medical Institute, The Rockefeller University, New York, USA
• Jean-Christophe Rain, Hybrigenics Services, Paris
• Marco Sandri, Venetian Institute of Molecular Medicine, Padova, Italy
• Odile Schiltz & Anne Gonzalez-de-Peredo, IPBS, Toulouse
• Ivo P Touw, Erasmus University, Rotterdam, The Netherlands
• Peter van der Ven, Institute of Cell Biology, Bonn, Germany
• Stéphane Zaffran, Université d’Aix Marseille, INSERM U1251, Marseille
Our previous and ongoing projects were/are supported by several grants and fellowships from:
• Agence Nationale de la Recherche
• Association Centpoursanglavie
• Association Française contre les Myopathies
• Fondation ARC pour la Recherche sur le Cancer
• Fondation de France
• Fondation pour la Recherche Médicale
• Fondation Recherche Innovation Thérapeutique Cancérologie
• Fondation Roland Garrigou pour la culture et la santé (Fonroga)
• Lady TATA Foundation
• Ligue Nationale contre le Cancer
• Réseau National de Génopoles
• Société Française d’Hématologie
• Université de Toulouse
• Camille A Spinner, Post-doctoral fellow, National Cancer Institute (NCI), National Institute of Health (NIH), Bethesda, USA
• Rim Zakaria, Attaché de Recherche Clinique, Toulouse
• Isabelle Lamsoul, CNRS Senior Research Associate, IPBS, Toulouse
• Christel Boutonnet, Research Associate, Toulouse White Biotechnology
• Clara F Burande, School Teacher
• Mélina L Heuzé, Assistant Professor, Institut Jacques Monod, Université Paris 7, Paris