Actin cytoskeleton organization and function in health and disease
openNIGMS - National Institute of General Medical Sciences
Project Summary/Abstract
The overarching goal of this proposal is to explore novel aspects of the actin cytoskeleton organization and
function in health and disease. The remarkable functional versatility of the actin cytoskeleton stems from its
ability to assemble into a variety of diverse structures – branched networks/meshes and aligned bundles. This
architectural complexity is orchestrated by actin-binding proteins, whose activity is delicately regulated in
response to internal and external signals. Human plastins are versatile actin-binding proteins that organize actin
filaments into higher-order assemblies: bundles and networks. Plastins are involved in cytokinesis, migration,
and stabilization of membrane protrusions, but also in the pathogenesis of the following diseases:
carcinogenesis, neurodegeneration, and hereditary and infectious diseases. Despite the importance and long-
lasting interest of the research community in these proteins, understanding of their interaction with actin and their
regulation is superficial. Our first research direction is to contribute to human health and well-being by advancing
the understanding of the actin cytoskeleton organization by actin-bundling proteins plastins and their contribution
to pathologies (e.g., congenital diseases and metastatic cancers) at the molecular and cellular levels.
Playing numerous vital roles in human defense mechanisms, the actin cytoskeleton is a common target for
numerous bacterial pathogens, which developed various elegant and sophisticated ways to disrupt and usurp it
by producing actin-targeting effectors. By hijacking the actin cytoskeleton, pathogenic toxins disturb cell
morphology, cell motility, phagocytosis, epithelial permeability, and antigen presentation. Being constantly
adjusted to the host cytoskeleton by co-evolution, they recognize weaknesses in the host defense and represent
powerful tools that foster the understanding of the cytoskeleton on molecular and cellular levels. The urge for a
thorough understanding of bacterial pathogenicity is further necessitated by the dissemination of multidrug-
resistant pathogens that undermine the efficiency of antibiotics. The second research direction of this proposal
is to decipher the in-depth molecular and cellular mechanisms of bacterial effectors targeting the actin
cytoskeleton to i) enable alternative ways of targeting pathogens and ii) get a deeper understanding of the actin
cytoskeleton per se.
The current proposal is directly relevant to the NIH mission as it focuses on three families of bacterial effectors,
all produced by human pathogens: Vibrio cholerae and Vibrio parahaemolyticus VopF/VopL (1) and VopM/VopV
(2), and Legionella pneumophila MavH, RavH, and VipA (3). Furthermore, the proposal is of interest for a general
understanding of human physiology as each of the above toxins reveals novel properties of the actin
cytoskeleton. Finally, the understanding of the molecular and cellular mechanisms governing the function of
actin-bundling proteins plastins contributes to explaining the pathology of plastin-related human diseases.
Up to $442K
health research