CeMM Scientific Director
Professor for Medical Systems Biology, Medical University of Vienna
Membrane Transporters, Metabolism & Drug Action
Key for any living entity, such as a human cell, is the ability to contain an own environment within membranes that not only preserves the genetic material, but also allows chemical reactions to be efficient and generate energy. Management of the interface between the external world and the biochemical self occurs through the activity and regulation of membrane transporters. The Superti-Furga laboratory considers transporters ideal means to tune the metabolism of cells while representing a manifestation of a cell’s appetite for nutrients integrated over the environment’s offer.
The GSF Lab science summarized in five points:
1. We investigate the mechanisms and the logic of how the concentration of individual metabolites, ions, nutrients is achieved, coordinated and maintained.
2. We study the role that different concentrations of small molecules within the cell and the cellular environment play on cellular identity, homeostasis and disease.
3. We perturb specific processes and pathways to alter metabolism and growth and thereby study their interdependence.
4. We have a strategic focus on membrane transporters as druggable key regulators of metabolism, and on proteostasis as druggable link between growth and metabolism.
5. It is also our ambition to foster translational research and focus on the design and discovery of small molecule drugs that alter homeostasis and on ex vivo assessment of drug action in cancer and inflammation.
Metabolism and regulation of metabolite concentration
All cells are surrounded by a lipid bilayer representing a “greasy seal” between the aqueous inside of the cell and the outside. Yet the cells need to import nutrients, water and ions to sustain their internal metabolism to produce energy and the building blocks required to safeguard and replicate the genetic material and the rest of the cellular infrastructure. While only a few molecules are thought to be able to pass through the lipid membrane surrounding cells, most molecules, including vitamins, small molecule hormones, xenobiotics, phytochemicals, pesticides, microbiome metabolites and, importantly, drugs require transporters to enter. The membrane transporters can thus be considered the managers of the interface between chemistry and biology and between organisms and their environment. As they are overall a large and neglected gene family in humans, we proposed to intensify and coordinate research on the largest group of membrane transporters in the human genome, the SLC solute carrier superfamily (César-Razquin, Snijder et al, Cell 2015). Membrane transporters, and their roles in metabolism, drug transport and signaling are being investigated heavily in the laboratory. A better understanding of the transport and signaling specificity of individual SLCs and their concerted circuits may on one hand lead to better targeted drugs and on the other hand pave the way for an understanding of how biological systems are integrated with their environment.
Cancer targets and drug discovery
Most drugs work not only by engaging a single target, but by producing large, complex perturbations of biological systems. In general, the expectation is that the systematic adoption of more rigorous and “systems-level” characterization of chemical entities will help understanding the biology of drug action better and allow the development of improved drugs. It should help the community in rationalizing patient stratification, thus increasing the efficacy of clinical trials and reduce unwanted side effects, but also contribute to the employment of mechanism-based combination therapy with existing drugs. In particular, the GSF lab has a long-standing interest in understanding the molecular wiring of transformed cells of the hematopoietic system, as well as studying the mode of action of targeted agents counteracting leukemia cell proliferation. Starting from BCR-ABL signaling in Chronic myeloid leukemia (CML) to different types of Acute myeloid leukemia (AML) as model system, we are using novel approaches to uncover novel therapeutic avenues and mechanisms of resistance towards targeted therapy.
Innate immunity, inflammation and infection
Understanding how the body responds to foreign threats, such as bacterial and viral infections, and how autoimmune defenses are triggered when these defenses go awry, can pave the way for novel treatments and therapeutic interventions in a multitude of disease states. Over the past decade, we have discovered a novel adaptor protein that connects the innate to the adaptive immune system, unraveled the role of SLCs in cell survival upon viral infection and phagocytosis in response to bacterial infection. We demonstrated the role of membrane lipid composition in the innate immune response and how targeting programmed cell death can be leveraged to combat inflammation.
Giulio Superti-Furga is an Italian molecular and systems biologist and Commander of the Order of Merit of the Italian Republic. He is Scientific Director of CeMM, research group leader at CeMM, and Professor for Systems Pharmacology at the Medical University of Vienna. From 2017 to 2019, he was a member of the Scientific Council of the European Research Council (ERC). He studied at University of Zurich, Genentech (San Francisco), and IMP (Vienna). He was a postdoctoral fellow and team leader at EMBL (Heidelberg). He co-founded the biotech companies Cellzome, Haplogen, Allcyte, Proxygen, and Solgate. His major scientific achievements include the elucidation of basic regulatory mechanisms of tyrosine kinases in human cancers, the discovery of fundamental organization principles of the proteome and metabolome of higher organisms, and the development of integrated approaches to understand the mechanism of drug action at the molecular level. Recently, he and his team discovered a novel innate immune adaptor (named TASL) and elucidated its mechanistic action. For the past seven years, he has focused on unlocking the human “transportome” for medicine and drug discovery, trying to de-orphanize members of the solute carrier family (SLCs) of membrane transporters and mapping their role in cell biology and drug transport. He is the academic coordinator of the Innovative Medicines Initiative (IMI) consortium “RESOLUTE”, which focuses on SLCs. He is a member of EMBO, the Austrian Academy of Sciences, the German Academy of Sciences Leopoldina, the European Academy of Cancer Sciences, and Academia Europaea.
Check here Giulio Superti-Furga’s genome: PGA-1
Pemovska T et al. Metabolic drug survey highlights cancer cell dependencies and vulnerabilities. Nature Communications. 2021 Dec; 12(1) 7190 (abstract)
Li et al. Cell-surface SLC nucleoside transporters and purine levels modulate BRD4-dependent chromatin states. Nature Metabolism. 2021; 3:651-664 (abstract)
Heinz et al. TASL is the SLC15A4-associated adaptor for IRF5activation by TLR7-9. Nature. 2020; 581:316-322. (abstract)
Girardi et al. Epistasis-driven identification of SLC25A51 as a regulator of human mitochondrial NAD import. Nature Communications. 2020; 11:6145. (abstract)
Meixner E et al. A substrate-based ontology for human solute carriers. Molecular Systems Biology. 2020 Jul; 16(7) (abstract)
Bensimon A et al. Targeted Degradation of SLC Transporters Reveals Amenability of Multi-Pass Transmembrane Proteins to Ligand-Induced Proteolysis. Cell Chemical Biology. 2020 Jun; 27(6) (abstract)
Fauster A et al. Systematic genetic mapping of necroptosis identifies SLC39A7 as modulator of death receptor trafficking. Cell Death Differentiation. 2019 Jun; 26(6) 1138-1155 (abstract)
Bigenzahn JW, et al. LZTR1 is a regulator of RAS ubiquitination and signaling. Science. 2018 Dec 7;362(6419):1171-1177. (abstract)
Vladimer GI*, Snijder B*, et al. Global survey of the immunomodulatory potential of common drugs. Nat Chem Biol. 2017;13(6):681-690. (abstract)
César-Razquin A, et al. A Call for Systematic Research on Solute Carriers. Cell. 2015 Jul 30;162(3):478-87. (abstract)
Rebsamen M, et al. SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1. Nature. 2015 Mar 26;519(7544):477-81. (abstract)
Köberlin MS, et al. A conserved circular network of coregulated lipids modulates innate immune responses. Cell. 2015;162(1):170-83. (abstract)
Huber KV, et al. Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. Nature. 2014 Apr 10;508(7495):222-7. (abstract)
Winter GE, et al. The solute carrier SLC35F2 enables YM155-mediated DNA damage toxicity. Nat Chem Biol. 2014 Sep;10(9):768-73. (abstract)
Pichlmair A, et al. Viral immune modulators perturb the human molecular network by common and unique strategies. Nature. 2012 Jul 26;487(7408):486-90. (abstract)
Winter GE, et al. Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML. Nat Chem Biol. 2012 Nov;8(11):905-12. (abstract)
Grebien F, et al. Targeting the SH2-kinase interface in Bcr-Abl inhibits leukemogenesis. Cell. 2011 Oct 14;147(2):306-19. (abstract)
Pichlmair A, et al. IFIT1 is an antiviral protein that recognizes 5'-triphosphate RNA. Nat Immunol. 2011 Jun 5;12(7):624-30. (abstract)
Bürckstümmer T, et al. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nat Immunol. 2009 Mar;10(3):266-72. (abstract)
Gavin AC, et al. Proteome survey reveals modularity of the yeast cell machinery. Nature. 2006 Mar 30;440(7084):631-6. (abstract)
Bouwmeester T, et al. A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nat Cell Biol. 2004 Feb;6(2):97-105. (abstract)
Hantschel O, et al. A myristoyl/phosphotyrosine switch regulates c-Abl. Cell. 2003 Mar 21;112(6):845-57. (abstract)
Gavin AC, et al. Functional organization of the yeast proteome by systematic analysis of protein complexes. Nature. 2002 Jan 10;415(6868):141-7. (abstract)