Please use this identifier to cite or link to this item: https://hdl.handle.net/20.500.12202/1373
Title: Lipid kinase PI4KIIIbeta preserves lysosomal identity
Authors: Sridhar, Sunandini
Keywords: Cellular biology.
Molecular biology.
Issue Date: 2012
Publisher: ProQuest Dissertations & Theses
Citation: Source: Dissertation Abstracts International, Volume: 74-06(E), Section: B.;Advisors: Ana Maria Cuervo.
Abstract: Lipid modifications are essential in cellular sorting and trafficking inside cells. The role of phosphoinositides in trafficking between Golgi and endocytic/lysosomal compartments has been extensively explored and the kinases responsible for these lipid changes have been identified. In contrast, the mechanisms that mediate exit and recycling from lysosomes, considered for a long time as terminal compartments, are less understood. The goal of this thesis research was to investigate the contribution of phosphoinositide PI(4)P and its cognate lipid kinase type-III phosphatidylinositol-4-kinasebeta (PI4KIIIbeta) to the spatio-temporal control of sorting events throughout the endolysosomal pathway and to characterize the possible physiological relevance of this control over lysosomal influx and efflux events. In this work, we identify a dynamic association of the lipid kinase PI4KIIIbeta with lysosomes and unveil its regulatory function in lysosomal export and retrieval.;In the first part of this thesis, we have found that absence of PI4KIIIbeta leads to abnormal formation of tubular structures from the lysosomal surface and loss of lysosomal constituents through these tubules. We have also identified a lysosome-associated catalytically active form of PI4KIIIbeta that we propose modulates cargo exit directly at the lysosomal membrane in a PI(4)P contingent manner. Moreover, proteomic analysis of cytosolic vesicles positive for PI4KIIIbeta confirmed its presence in vesicles carrying lysosomal components and aided identification of the coat-forming and adaptor proteins recruited to lysosomes in a PI4KIIIbeta-PI(4)P-dependent manner.;In the second part of this thesis, we demonstrate that the lysosomal function of PI4KIIIbeta is necessary to prevent unwanted lysosomal efflux and to facilitate proper sorting when recycling of lysosomal material is needed, in the physiological context of lysosomal reformation after prolonged starvation and antigen presentation. Moreover, we found that PI4KIIIbeta levels change reciprocally at the lysosome and the Golgi under refeeding conditions and that during conditions of nutritional deprivation, the Golgi-associated PI4KIIIbeta selectively undergoes degradation in lysosomes through chaperone-mediated autophagy. We propose that PI4KIIIbeta serves to integrate signals from physiological switches with regulation of the Golgi and lysosome homeostasis. This work delineates a hitherto uncharacterized function for PI4KIIIbeta and its product PI(4)P in regulating lysosomal exit and thus, in maintenance of lysosomal identity.
URI: https://ezproxy.yu.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:3537102
https://hdl.handle.net/20.500.12202/1373
Appears in Collections:Albert Einstein College of Medicine: Doctoral Dissertations

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