We interrogate the mechanisms by which cells convert membrane surfaces into high-definition signaling screens. We focus on lipid metabolism and signaling in that regard, and the laboratory deploys diverse approaches to address the fundamental questions. We employ genetic, cell biological, imaging, biochemical, biophysical, structural, and computational methods, and the model experimental systems currently include yeast, mice, and the obligate eukaryotic parasite Toxoplasma. Our research addresses questions regarding brain development, etiologies of autism and neurodegeneration, and cancer biology. Moreover, we have active projects in the design of new generation lead compounds for the development of antibiotics directed against fungal pathogens.
Lipid exchange proteins
We are interested in solving the ‘problem’ of how lipid signaling is physically organized and regulated on membrane surfaces with a focus on how phosphatidylinositol transfer proteins (PITPs) control these parameters at physiological, cell biological, and single-molecule levels. PITPs interface with phosphoinositide signaling pathways and organizing, diversifying, and otherwise channeling the activities of lipid kinases towards specific biological outcomes. PITPs represent a fascinating class of proteins that potentiate and instruct phosphatidylinositol kinase activities by helping these enzymes solve the problem of interfacial catalysis. Although yeast and plant systems represent the major model systems we use in these studies, the fact that inherited mammalian diseases (e.g., vitamin E-responsive and Cayman ataxia, dystonia, retinal degeneration, basal cell carcinoma, etc.) result from defects in Sec14-like PITPs testifies to the biological impact of these proteins.
C. Mousley, P. Yuan, N. A. Gaur, K. D. Trettin, A. H. Nile, S. Deminoff, B. J. Dewar, M. Wolpert, J. M. Macdonald, P. K. Herman, A. G. Hinnebusch, V. A. Bankaitis, A sterol binding protein integrates endosomal lipid metabolism with TOR signaling and nitrogen sensing. Cell 148, 702–715 (2012).
Y. Wang, P. Yuan, A. Grabon, A. Tripathi, D. Lee, M. Rodriguez, M. Lönnfors, M. Eisenberg-Bord, Z. Wang, S. M. Lam, M. Schuldiner, V. A. Bankaitis, Non-canonical regulation of phosphatidylserine metabolism by a Sec14-like protein and a lipid kinase. J. Cell Biol. 219 (2020).
Chemical biology and drug design
A significant effort in the lab falls into the area of discovery and design of new anti-fungal compounds. We identified and validated the first highly specific small molecule inhibitors (SMIs) directed against individual fungal Sec14-like PITPs, and defined a facile platform for in vivo and in vitro target validation for such SMIs. From the fundamental experimental perspective, PITP-directed SMIs represent powerful tools for exquisitely selective inhibition of specific phosphoinositide signaling pathways in vivo. From the applied human health perspective, our advances in describing the structural basis for Sec14:: drug interactions now enable rational design of next-generation SMIs that target Sec14-like proteins of emerging fungal pathogens that are proving deadly to humans.
A. Y. Lee, R. P. St. Onge, M. J. Proctor, I. M. Wallace, A. H. Nile, P. A. Spanguolo, Y. Jitkova, M. Gronda, Y. Wu, M. K. Kim, K. Cheung-Ong, N. P. Torres, E. D. Spear, M. K. L. Han, U. Schlecht, S. Suresh, G. Duby, L. E. Heisler, A. Surendra, E. Fung, M. L. Urbanus, M. Gebbia, E. Lissina, M. Miranda, J. H. Chiang, A. M. Aparicio, M. Zeghouf, R. W. Davis, J. Cherfils, M. Boutry, C. A. Kaiser, C. L. Cummins, W. S. Trimble, G. W. Brown, A. D. Schimmer, V. A. Bankaitis, C. Nislow, G. D. Bader, G. Giaever, Mapping the cellular response to small molecules using chemogenomic fitness signatures. Science 344, 208–211 (2014).
K. R. Roy, J. D. Smith, S. C. Vonesch, G. Lin, C. Szu Tu, A. R. Lederer, A. Chu, S. Suresh, M. Nguyen, J. Horecka, A. Tripathi, W. T. Burnett, M. A. Morgan, J. Schulz, K. M. Orsley, W. Wei, R. S. Aiyar, R. W. Davis, V. A. Bankaitis, J. E. Haber, M. L. Salit, R. P. St.Onge, L. M. Steinmetz, Multiplexed precision genome editing with trackable genomic barcodes. Nat. Biotechnol. 36, 512–520 (2018).
We have leveraged what we learned about Sec14 in yeast and applied our experimental platform to mammalian PITPs. We created the first PITP null mice (phenotypes including rapid onset spinocerebellar neurodegeneration, chylomicron retention disease, and neonatal death). They isolated the first PITP lipid-binding mutants, and first demonstrated that the lipid-binding activities are essential properties of a mammalian PITP in vivo. Using technology to genetically manipulate embryonic neural stem cells in an unperturbed neurological niche (i.e., the real brain), we are studying a novel PITP-dependent pathway essential for establishing and maintaining neural stem cell polarity in mammals and flies. We are also engaged in studies using PITP knockout mice in several cancer biology projects that interrogate the relationship between metastasis and phosphoinositide signaling in the Golgi system. Moreover, we apply atomistic molecular dynamics to model the initial stages of the PITP lipid exchange cycle. A new direction that has grown from these studies is the study of unique multi-domain PITPs in obligate intracellular apicomplexan parasites such as Toxoplasma.
A. Grabon, A. Orlowski, A. Tripathi, J. Vuorio, M. Javanainen, T. Rog, M. Lönnfors, G. Siebert, M. I. McDermott, P. Somerharju, I. Vattulainen, V. A. Bankaitis, Atomistic insights into the dynamics and energetics of the mammalian phosphatidylinositol transfer protein phospholipid exchange cycle. J. Biol. Chem. 292, 14438–14455. (2017).
C. T. Koe, Y. S. Tan, M. Lönnfors, S. K. Hur, C. S. L. Low, Y. Zhang, F. Yu, P. Kanchanawong, V. A. Bankaitis, H. Wang, Vibrator and PI4KIIIα govern neuroblast polarity by anchoring non-muscle myosin II. eLife 7 (2018).
The lab is engaged in significant neural stem cell (NSC) biology efforts from the perspective of inborn errors of lipid metabolism and susceptibility to neurodevelopmental disorders such as autism spectrum diseases. This new line of inquiry is enjoying considerable extramural interest from the biomedical and the lay communities as it outlines new approaches for gauging, and managing, a significant component of autism risk in humans.
V. A. Bankaitis and Z. Xie, New autism research: A nutrient called carnitine might counteract gene mutations linked with ASD risk. The Conversation (2016).
V. A. Bankaitis and Z. Xie, The neural stem cell/carnitine malnutrition hypothesis: New prospect for effective reduction of autism risk. J. Biol. Chem. 294, 19424–19435 (2019).
To Academic Professional Track Faculty