Kent L Hill
Professor, MIMG, University of California Los Angeles
Los Angeles, CA 90095
Los Angeles, CA 90095
Work Phone Number:
The eukaryotic flagellum (synonymous with cilium) is a biological nanomachine, composed of thousands of interconnected parts. Flagella and cilia perform essential motility and signaling functions, are conserved in all eukaryotic lineages, and are considered to have been present on the last eukaryotic common ancestor.
Proteomics and genomics have provided an inventory of flagellar proteins, but we lack knowledge of how these are assembled into supramolecular structures that operate individually and collectively to drive motility and signaling by the flagellum. This presents a critical gap in our understanding of one of the most iconic features of eukaryote biology. To fill this gap, we use cryoelectron microscopy (cryoEM) and tomography (cryoET) to determine the 3D architecture of the flagellum. We also employ proteomics, super-resolution microscopy, high-speed video microscopy and animal imaging to define the spatial distribution of proteins within flagellum micro-domains, investigate mechanisms of microbial cell and signaling, and determine how the flagellum controls virulence of microbial pathogens. Our goal is to provide a structural foundation for defining flagellum motility and signaling mechanisms at the molecular level, with models being formally tested through genetic manipulation of component parts.
As an experimental system, my group employs African trypanosomes, parasites that present a global public health burden and limit economic development in some of the most impoverished regions on the planet. The flagellum directs parasite motility and extracellular sensing and is thus essential for transmission and pathogenic capacity of these deadly organisms.
The trypanosome flagellum is also conserved with the human cilium (aka flagellum), which is essential for normal development and physiology. Indeed, cilium defects underlie a broad spectrum of inherited diseases, including retinopathy, renal failure, skeletal abnormalities and obesity. Therefore, beyond their medical and economic importance, trypanosomes are an important model system for studying flagellum/cilium biology. They are easily cultured for biochemical studies and possess a potent array of molecular genetic tools for targeted gene knockout and inducible RNAi. The genome is fully sequenced and annotated and systems biology approaches, e.g. transcriptomics, quantitative proteomics and high-throughput RNAi screens, are well established. Therefore, in addition to host-pathogen interaction, we use our studies to advance understanding of inherited diseases in humans, and provide insights into fundamental features of eukaryotic cell biology.
- Zhang J, Wang H, Imhof S, Zhou X, Liao S, Atanasov I, Hui WH, Hill KL, Zhou ZH. Author Correction: Structure of the trypanosome paraflagellar rod and insights into non-planar motility of eukaryotic cells.. Cell discovery, 2021.
- Zhang J, Wang H, Imhof S, Zhou X, Liao S, Atanasov I, Hui WH, Hill KL, Zhou ZH. Structure of the trypanosome paraflagellar rod and insights into non-planar motility of eukaryotic cells.. Cell discovery, 2021.
- Walsh B, Hill KL. Right place, right time: Environmental sensing and signal transduction directs cellular differentiation and motility in Trypanosoma brucei.. Molecular microbiology, 2021.
- Vélez-Ramírez DE, Shimogawa MM, Ray SS, Lopez A, Rayatpisheh S, Langousis G, Gallagher-Jones M, Dean S, Wohlschlegel JA, Hill KL. APEX2 Proximity Proteomics Resolves Flagellum Subdomains and Identifies Flagellum Tip-Specific Proteins in Trypanosoma brucei.. mSphere, 2021.
- DeMarco SF, Saada EA, Lopez MA, Hill KL. Identification of Positive Chemotaxis in the Protozoan Pathogen Trypanosoma brucei.. mSphere, 2020.
- Imhof S, Zhang J, Wang H, Bui KH, Nguyen H, Atanasov I, Hui WH, Yang SK, Zhou ZH, Hill KL. Cryo electron tomography with volta phase plate reveals novel structural foundations of the 96-nm axonemal repeat in the pathogen Trypanosoma brucei.. eLife, 2019.
- Shaw S, DeMarco SF, Rehmann R, Wenzler T, Florini F, Roditi I, Hill KL. Flagellar cAMP signaling controls trypanosome progression through host tissues.. Nature communications, 2019.
- Zhang Y, Ceylan Koydemir H, Shimogawa MM, Yalcin S, Guziak A, Liu T, Oguz I, Huang Y, Bai B, Luo Y, Luo Y, Wei Z, Wang H, Bianco V, Zhang B, Nadkarni R, Hill K, Ozcan A. Motility-based label-free detection of parasites in bodily fluids using holographic speckle analysis and deep learning.. Light, science & applications, 2018.
- Shimogawa MM, Ray SS, Kisalu N, Zhang Y, Geng Q, Ozcan A, Hill KL. Parasite motility is critical for virulence of African trypanosomes.. Scientific reports, 2018.
- Marti M, Hill KL. Sensing and signaling in parasitism.. Molecular and biochemical parasitology, 2016.
- Langousis G, Shimogawa MM, Saada EA, Vashisht AA, Spreafico R, Nager AR, Barshop WD, Nachury MV, Wohlschlegel JA, Hill KL. Loss of the BBSome perturbs endocytic trafficking and disrupts virulence of Trypanosoma brucei.. Proceedings of the National Academy of Sciences of the United States of America, 2015.
- Saada EA, DeMarco SF, Shimogawa MM, Hill KL. "With a Little Help from My Friends"-Social Motility in Trypanosoma brucei.. PLoS pathogens, 2015.
- Shimogawa MM, Saada EA, Vashisht AA, Barshop WD, Wohlschlegel JA, Hill KL. Cell Surface Proteomics Provides Insight into Stage-Specific Remodeling of the Host-Parasite Interface in Trypanosoma brucei.. Molecular & cellular proteomics : MCP, 2015.
- Oberholzer M, Saada EA, Hill KL. Cyclic AMP Regulates Social Behavior in African Trypanosomes.. mBio, 2015.
- Lopez MA, Saada EA, Hill KL. Insect stage-specific adenylate cyclases regulate social motility in African trypanosomes.. Eukaryotic cell, 2014.
- Langousis G, Hill KL. Motility and more: the flagellum of Trypanosoma brucei.. Nature reviews. Microbiology, 2014.
- Freire ER, Vashisht AA, Malvezzi AM, Zuberek J, Langousis G, Saada EA, Nascimento Jde F, Stepinski J, Darzynkiewicz E, Hill K, De Melo Neto OP, Wohlschlegel JA, Sturm NR, Campbell DA. eIF4F-like complexes formed by cap-binding homolog TbEIF4E5 with TbEIF4G1 or TbEIF4G2 are implicated in post-transcriptional regulation in Trypanosoma brucei.. RNA (New York, N.Y.), 2014.
- Saada EA, Kabututu ZP, Lopez M, Shimogawa MM, Langousis G, Oberholzer M, Riestra A, Jonsson ZO, Wohlschlegel JA, Hill KL. Insect stage-specific receptor adenylate cyclases are localized to distinct subdomains of the Trypanosoma brucei Flagellar membrane.. Eukaryotic cell, 2014.
- Freire ER, Malvezzi AM, Vashisht AA, Zuberek J, Saada EA, Langousis G, Nascimento JD, Moura D, Darzynkiewicz E, Hill K, de Melo Neto OP, Wohlschlegel JA, Sturm NR, Campbell DA. Trypanosoma brucei translation initiation factor homolog EIF4E6 forms a tripartite cytosolic complex with EIF4G5 and a capping enzyme homolog.. Eukaryotic cell, 2014.
- Kisalu NK, Langousis G, Bentolila LA, Ralston KS, Hill KL. Mouse infection and pathogenesis by Trypanosoma brucei motility mutants.. Cellular microbiology, 2014.
- Nguyen HT, Sandhu J, Langousis G, Hill KL. CMF22 is a broadly conserved axonemal protein and is required for propulsive motility in Trypanosoma brucei.. Eukaryotic cell, 2013.
- Freund JB, Goetz JG, Hill KL, Vermot J. Fluid flows and forces in development: functions, features and biophysical principles.. Development (Cambridge, England), 2012.
- Hughes LC, Ralston KS, Hill KL, Zhou ZH. Three-dimensional structure of the Trypanosome flagellum suggests that the paraflagellar rod functions as a biomechanical spring.. PloS one, 2012.
- Lopez MA, Nguyen HT, Oberholzer M, Hill KL. Social parasites.. Current opinion in microbiology, 2011.
- Oberholzer M, Langousis G, Nguyen HT, Saada EA, Shimogawa MM, Jonsson ZO, Nguyen SM, Wohlschlegel JA, Hill KL. Independent analysis of the flagellum surface and matrix proteomes provides insight into flagellum signaling in mammalian-infectious Trypanosoma brucei.. Molecular & cellular proteomics : MCP, 2011.
- Ralston KS, Kisalu NK, Hill KL. Structure-function analysis of dynein light chain 1 identifies viable motility mutants in bloodstream-form Trypanosoma brucei.. Eukaryotic cell, 2011.
- Kabututu ZP, Thayer M, Melehani JH, Hill KL. CMF70 is a subunit of the dynein regulatory complex.. Journal of cell science, 2010.
- Hill KL. Parasites in motion: flagellum-driven cell motility in African trypanosomes.. Current opinion in microbiology, 2010.
- Oberholzer M, Lopez MA, McLelland BT, Hill KL. Social motility in african trypanosomes.. PLoS pathogens, 2010.
- Oberholzer M, Lopez MA, Ralston KS, Hill KL. Approaches for functional analysis of flagellar proteins in African trypanosomes.. Methods in cell biology, 2009.
- Rodríguez JA, Lopez MA, Thayer MC, Zhao Y, Oberholzer M, Chang DD, Kisalu NK, Penichet ML, Helguera G, Bruinsma R, Hill KL, Miao J. Propulsion of African trypanosomes is driven by bihelical waves with alternating chirality separated by kinks.. Proceedings of the National Academy of Sciences of the United States of America, 2009.
- Ralston KS, Kabututu ZP, Melehani JH, Oberholzer M, Hill KL. The Trypanosoma brucei flagellum: moving parasites in new directions.. Annual review of microbiology, 2009.
- Colantonio JR, Vermot J, Wu D, Langenbacher AD, Fraser S, Chen JN, Hill KL. The dynein regulatory complex is required for ciliary motility and otolith biogenesis in the inner ear.. Nature, 2008.
- Ralston KS, Hill KL. The flagellum of Trypanosoma brucei: new tricks from an old dog.. International journal for parasitology, 2008.
- Bekker JM, Colantonio JR, Stephens AD, Clarke WT, King SJ, Hill KL, Crosbie RH. Direct interaction of Gas11 with microtubules: implications for the dynein regulatory complex.. Cell motility and the cytoskeleton, 2007.
- Baron DM, Kabututu ZP, Hill KL. Stuck in reverse: loss of LC1 in Trypanosoma brucei disrupts outer dynein arms and leads to reverse flagellar beat and backward movement.. Journal of cell science, 2007.
- Baron DM, Ralston KS, Kabututu ZP, Hill KL. Functional genomics in Trypanosoma brucei identifies evolutionarily conserved components of motile flagella.. Journal of cell science, 2007.
- Ralston KS, Hill KL. Trypanin, a component of the flagellar Dynein regulatory complex, is essential in bloodstream form African trypanosomes.. PLoS pathogens, 2006.
- Colantonio JR, Bekker JM, Kim SJ, Morrissey KM, Crosbie RH, Hill KL. Expanding the role of the dynein regulatory complex to non-axonemal functions: association of GAS11 with the Golgi apparatus.. Traffic (Copenhagen, Denmark), 2006.
- Ralston KS, Lerner AG, Diener DR, Hill KL. Flagellar motility contributes to cytokinesis in Trypanosoma brucei and is modulated by an evolutionarily conserved dynein regulatory system.. Eukaryotic cell, 2006.
- Hill KL. Biology and mechanism of trypanosome cell motility.. Eukaryotic cell, 2003.
- Yi CE, Bekker JM, Miller G, Hill KL, Crosbie RH. Specific and potent RNA interference in terminally differentiated myotubes.. The Journal of biological chemistry, 2002.
- Hutchings NR, Donelson JE, Hill KL. Trypanin is a cytoskeletal linker protein and is required for cell motility in African trypanosomes.. The Journal of cell biology, 2002.