PKD2 regulates autophagy and forms a protein complex with BECN1 at the primary cilium of hypothalamic neuronal cells.

Autor: García-Navarrete C; Instituto de Investigación en Ciencias Odontológicas (ICOD), Facultad de Odontología, Universidad de Chile, Santiago, Chile., Kretschmar C; Instituto de Investigación en Ciencias Odontológicas (ICOD), Facultad de Odontología, Universidad de Chile, Santiago, Chile., Toledo J; Advanced Scientific Equipment Network (REDECA), Facultad de Medicina, Universidad de Chile, Chile., Gutiérrez K; Instituto de Investigación en Ciencias Odontológicas (ICOD), Facultad de Odontología, Universidad de Chile, Santiago, Chile., Hernández-Cáceres MP; Instituto de Investigación en Ciencias Odontológicas (ICOD), Facultad de Odontología, Universidad de Chile, Santiago, Chile; Department of Basic Sciences, Faculty of Medicine and Sciences, Universidad San Sebastián, Santiago, Chile., Budini M; Instituto de Investigación en Ciencias Odontológicas (ICOD), Facultad de Odontología, Universidad de Chile, Santiago, Chile; Autophagy Research Center, Santiago, Chile., Parra V; Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas & Farmacéuticas, Universidad de Chile, Santiago, Chile; Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas & Farmacéuticas & Facultad Medicina, Universidad de Chile, Santiago, Chile., Burgos PV; Autophagy Research Center, Santiago, Chile; Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile; Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Avenida Del Valle Norte #725, Huechuraba 8580702, Santiago, Chile., Lavandero S; Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas & Farmacéuticas, Universidad de Chile, Santiago, Chile; Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas & Farmacéuticas & Facultad Medicina, Universidad de Chile, Santiago, Chile; Cardiology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States., Morselli E; Department of Basic Sciences, Faculty of Medicine and Sciences, Universidad San Sebastián, Santiago, Chile; Autophagy Research Center, Santiago, Chile., Peña-Oyarzún D; Instituto de Investigación en Ciencias Odontológicas (ICOD), Facultad de Odontología, Universidad de Chile, Santiago, Chile; Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas & Farmacéuticas & Facultad Medicina, Universidad de Chile, Santiago, Chile; Faculty of Odontology and Rehabilitation Sciences, Universidad San Sebastián, Chile. Electronic address: daniel.pena@uss.cl., Criollo A; Instituto de Investigación en Ciencias Odontológicas (ICOD), Facultad de Odontología, Universidad de Chile, Santiago, Chile; Autophagy Research Center, Santiago, Chile; Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas & Farmacéuticas & Facultad Medicina, Universidad de Chile, Santiago, Chile. Electronic address: alcriollo@u.uchile.cl.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2024 Aug; Vol. 1870 (6), pp. 167256. Date of Electronic Publication: 2024 May 21.
DOI: 10.1016/j.bbadis.2024.167256
Abstrakt: The primary cilium, hereafter cilium, is an antenna-like organelle that modulates intracellular responses, including autophagy, a lysosomal degradation process essential for cell homeostasis. Dysfunction of the cilium is associated with impairment of autophagy and diseases known as "ciliopathies". The discovery of autophagy-related proteins at the base of the cilium suggests its potential role in coordinating autophagy initiation in response to physiopathological stimuli. One of these proteins, beclin-1 (BECN1), it which is necessary for autophagosome biogenesis. Additionally, polycystin-2 (PKD2), a calcium channel enriched at the cilium, is required and sufficient to induce autophagy in renal and cancer cells. We previously demonstrated that PKD2 and BECN1 form a protein complex at the endoplasmic reticulum in non-ciliated cells, where it initiates autophagy, but whether this protein complex is present at the cilium remains unknown. Anorexigenic pro-opiomelanocortin (POMC) neurons are ciliated cells that require autophagy to maintain intracellular homeostasis. POMC neurons are sensitive to metabolic changes, modulating signaling pathways crucial for controlling food intake. Exposure to the saturated fatty acid palmitic acid (PA) reduces ciliogenesis and inhibits autophagy in these cells. Here, we show that PKD2 and BECN1 form a protein complex in N43/5 cells, an in vitro model of POMC neurons, and that both PKD2 and BECN1 locate at the cilium. In addition, our data show that the cilium is required for PKD2-BECN1 protein complex formation and that PA disrupts the PKD2-BECN1 complex, suppressing autophagy. Our findings provide new insights into the mechanisms by which the cilium controls autophagy in hypothalamic neuronal cells.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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