Negative modulation of macroautophagy by HERPUD1 is counteracted by an increased ER-lysosomal network with impact in drug-induced stress cell survival
Negative modulation of macroautophagy by HERPUD1 is counteracted by an increased ER-lysosomal network with impact in drug-induced stress cell survival
ABSTRACT Macroautophagy and the ubiquitin proteasome system work as an interconnected network in the maintenance of cellular homeostasis. Indeed, efficient activation of macroautophagy upon nutritional deprivation is sustained by degradation of preexisting proteins by the proteasome. However, the specific substrates that are degraded by the proteasome in order to activate macroautophagy are currently unknown. By quantitative proteomic analysis we identified several proteins downregulated in response to starvation but independently of ATG5 expression. Among them, the most significant was HERPUD1, an ER protein of short-half life and a well-known substrate of the proteasome. We found that increased HERPUD1 stability by deletion of its ubiquitin-like domain (UBL) plays a negative role on basal and induced macroautophagy. Moreover, we found it triggers ER expansion by reordering the ER in crystalloid structures, but in the absence of unfolded protein response activation. Surprisingly, we found ER expansion led to an increase in the number and function of lysosomes establishing a tight network with the presence of membrane-contact sites. Importantly, a phosphomimetic S59D mutation within the UBL mimics UBL deletion on its stability and the ER-lysosomal network expansion revealing an increase of cell survival under stress conditions. Altogether, we propose stabilized HERPUD1 downregulates macroautophagy favoring instead a closed interplay between the ER and lysosomes with consequences in drug-cell stress survival. biorxiv;2021.06.14.447273v2/UFIG1F1ufig1
Arias-Mu?oz E.、Hern¨￠ndez S.、Cerda-Troncoso C.、Gonz¨￠lez A. E.、Tatham M. H.、Retamal C.、Rojas-Fernandez A.、Bustamante H.、Burgos P. V.、Hern¨￠ndez L.、Varas-Godoy M.、Cavieres V. A.、Cort¨|s O.、Cancino J.、Vargas G.、Hay R. T.
Centro de Biolog¨aa Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebasti¨￠n||Centro de Envejecimiento y Regeneraci¨?n (CARE-UC), Facultad de Ciencias Biol¨?gicas, Pontificia Universidad Cat¨?licaCentro de Biolog¨aa Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebasti¨￠nCentro de Biolog¨aa Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebasti¨￠nInstituto de Fisiolog¨aa, Facultad de Medicina, Universidad Austral de ChileCenter for Gene Regulation and Expression, College of Life Sciences, University of DundeeCentro de Biolog¨aa Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebasti¨￠nCenter for Gene Regulation and Expression, College of Life Sciences, University of Dundee||Instituto de Medicina & Centro Interdisciplinario de Estudios del Sistema Nervioso (CISNe), Universidad Austral de ChileInstituto de Microbiolog¨aa Cl¨anica, Facultad de Medicina, Universidad Austral de ChileCentro de Biolog¨aa Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebasti¨￠n||Centro de Envejecimiento y Regeneraci¨?n (CARE-UC), Facultad de Ciencias Biol¨?gicas, Pontificia Universidad Cat¨?licaCentro de Biolog¨aa Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebasti¨￠nCentro de Biolog¨aa Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebasti¨￠nCentro de Biolog¨aa Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebasti¨￠n||Centro de Envejecimiento y Regeneraci¨?n (CARE-UC), Facultad de Ciencias Biol¨?gicas, Pontificia Universidad Cat¨?licaCentro de Biolog¨aa Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebasti¨￠nCentro de Biolog¨aa Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebasti¨￠nCentro de Biolog¨aa Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebasti¨￠nCenter for Gene Regulation and Expression, College of Life Sciences, University of Dundee
基础医学细胞生物学生物化学分子生物学
Arias-Mu?oz E.,Hern¨￠ndez S.,Cerda-Troncoso C.,Gonz¨￠lez A. E.,Tatham M. H.,Retamal C.,Rojas-Fernandez A.,Bustamante H.,Burgos P. V.,Hern¨￠ndez L.,Varas-Godoy M.,Cavieres V. A.,Cort¨|s O.,Cancino J.,Vargas G.,Hay R. T..Negative modulation of macroautophagy by HERPUD1 is counteracted by an increased ER-lysosomal network with impact in drug-induced stress cell survival[EB/OL].(2025-03-28)[2025-04-26].https://www.biorxiv.org/content/10.1101/2021.06.14.447273.点此复制
评论