Interaction between HspA1A, a seventy-kDa heat shock protein, and lipids in stressed cells
Project Number5SC3GM121226-08
Former Number5SC3GM121226-04
Contact PI/Project LeaderNIKOLAIDIS, NIKOLAS
Awardee OrganizationCALIFORNIA STATE UNIVERSITY FULLERTON
Description
Abstract Text
PROJECT SUMMARY
HSPA1A is a stress-inducible seventy-kilodalton heat shock protein that plays essential roles in tumor cell
survival. This protein also localizes at the cell-surface and the extracellular medium of stressed and cancer
cells. HSPA1A-membrane positive tumors are resistant to radiation therapy, show increased invasiveness, and
develop distant metastasis, while membrane-bound and extracellular HSPA1A exert both immunostimulatory
and immunosuppressive functions. Recent research revealed that HSPA1A's membrane localization depends
on its selective interaction with specific lipids and the protein's extracellular transport is mediated by several
mechanisms including exosomes, secretory lysosomes, and lipid rafts. However, the trafficking of HSPA1A
towards the cell surface, the relationship between membrane-bound and extracellular HSPA1A, and the
specific lipid or protein modifications that trigger HSPA1A's re-localization remain unknown. To answer these
fundamental questions, we propose to characterize the trafficking mechanism of HSPA1A's membrane
translocation by determining the mechanism by which lipid interactions recruit HSPA1A to endosomal pathway.
This objective will be achieved by determining the re-localization pattern of HSPA1A in different subcellular
compartments after heat shock using subcellular fractionation and imaging, and depleting specific endosomal
lipids with drugs or lipid-biosensors. Furthermore, we will determine whether HSPA1A's extracellular transport
depends on its membrane localization and binding to specific lipids. To this end, we will delineate the
relationship between membrane-bound and extracellular HSPA1A, and then measure extracellular HSPA1A in
the presence or absence of the endo/exosomal pathway inhibitors and lipid-biosensors. Lastly, we will
characterize the lipid composition alterations and post-translational modifications on HSPA1A that affect its
membrane localization. To determine these changes, we will characterize the dynamics of the lipid composition
in stressed-cells, using a targeted lipidomics approach, and identify the differentially expressed lipid modifying
genes. Additionally, we will determine whether specific post-translational modifications on HSPA1A are
responsible for the increased membrane-bound HSPA1A using a targeted proteomics approach. This proposal
will provide fundamental knowledge that will form the basis for future interventions to control membrane-
associated and extracellular HSPA1A aiming to decrease tumor survival and increase the immune response.
Furthermore, this project will train multiple non-traditional and first-generation undergraduate and master level
students, and will prepare them for diverse careers in science.
Public Health Relevance Statement
PROJECT NARRATIVE
The research described in this proposal focuses on understanding how HSPA1A localizes at the cell surface
and outside of stressed and cancer cells. The characterization of this mechanism will allow devising of new
ways to render these cells sensitive to conventional therapies and activate the immune system against them.
No Sub Projects information available for 5SC3GM121226-08
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