TY - JOUR
T1 - Differential activation of eMI by distinct forms of cellular stress
AU - Mesquita, Ana
AU - Glenn, James
AU - Jenny, Andreas
N1 - Funding Information:
We thank Drs. N. Baker, H. Chang, G. Juhasz, K. McKim, M. Mlodzik, T. Neufeld, H. D. Ryoo, J. Sekelsky, W. Theurkauf, T. Vaccari, U. Weber, and the Vienna Drosophila Resource and Bloomington Drosophila Stock centers for kindly sharing fly strains. We thank Drs. Mimi Kim (Division of Biostatistics, Einstein) and Ana Maria Cuervo for advice and Drs. J. Secombe and H. Bülow for their comments on this manuscript. We thank the Einstein Analytical Imaging Facility (Grant # P30CA013330). This work was supported by AHA postdoctoral fellowship 18POST34030231 (to A.M) and NIH/NIGMS grant GM119160 (to A.J.).
Funding Information:
This work was supported by the American Heart Association [18POST34030231]; National Institute of General Medical Sciences [GM119160]. We thank Drs. N. Baker, H. Chang, G. Juhasz, K. McKim, M. Mlodzik, T. Neufeld, H. D. Ryoo, J. Sekelsky, W. Theurkauf, T. Vaccari, U. Weber, and the Vienna Drosophila Resource and Bloomington Drosophila Stock centers for kindly sharing fly strains. We thank Drs. Mimi Kim (Division of Biostatistics, Einstein) and Ana Maria Cuervo for advice and Drs. J. Secombe and H. B?low for their comments on this manuscript. We thank the Einstein Analytical Imaging Facility (Grant # P30CA013330). This work was supported by AHA postdoctoral fellowship 18POST34030231 (to A.M) and NIH/NIGMS grant GM119160 (to A.J.).
Publisher Copyright:
© 2020, © 2020 Informa UK Limited, trading as Taylor & Francis Group.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020
Y1 - 2020
N2 - As one of the major, highly conserved catabolic pathways, autophagy delivers cytosolic components to lysosomes for degradation. It is essential for development, cellular homeostasis, and coping with stress. Reduced autophagy increases susceptibility to protein aggregation diseases and leads to phenotypes associated with aging. Of the three major forms of autophagy, macroautophagy (MA) can degrade organelles or aggregated proteins, and chaperone-mediated autophagy is specific for soluble proteins containing KFERQ-related targeting motifs. During endosomal microautophagy (eMI), cytoplasmic proteins are engulfed into late endosomes in an ESCRT machinery-dependent manner. eMI can be KFERQ-specific or occur in bulk and be induced by prolonged starvation. Its physiological regulation and function, however, are not understood. Here, we show that eMI in the Drosophila fat body, akin to the mammalian liver, is induced upon oxidative or genotoxic stress in an ESCRT and partially Hsc70-4-dependent manner. Interestingly, eMI activation is selective, as ER stress fails to elicit a response. Intriguingly, we find that reducing MA leads to a compensatory enhancement of eMI, suggesting a tight interplay between these degradative processes. Furthermore, we show that mutations in DNA damage response genes are sufficient to trigger eMI and that the response to oxidative stress is under the control of MAPK/JNK signaling. Our data suggest that, controlled by various signaling pathways, eMI allows an organ to react and adapt to specific types of stress and is thus likely critical to prevent disease. Abbreviations: Atg: autophagy-related; CMA: chaperone-mediated autophagy; DDR: DNA damage repair; Df: deficiency (deletion); (E)GFP: (enhanced) green fluorescent protein; eMI: endosomal microautophagy; ER: endoplasmatic reticulum; ESCRT: endosomal sorting complexes required for transport; Eto: etoposide; FLP: flipase; Hsc: heat shock cognate protein; LAMP2A: lysosomal-associated membrane protein 2A; LE: late endosome; MA: macroautophagy; MI: microautophagy; MVB: multivesicular body; PA: photoactivatable; Para: paraquat; ROS: reactive oxygen species; SEM: standard error of means; Tor: target of rapamycin [serine/threonine kinase]; UPR: unfolded protein response; Vps: vacuolar protein sorting.
AB - As one of the major, highly conserved catabolic pathways, autophagy delivers cytosolic components to lysosomes for degradation. It is essential for development, cellular homeostasis, and coping with stress. Reduced autophagy increases susceptibility to protein aggregation diseases and leads to phenotypes associated with aging. Of the three major forms of autophagy, macroautophagy (MA) can degrade organelles or aggregated proteins, and chaperone-mediated autophagy is specific for soluble proteins containing KFERQ-related targeting motifs. During endosomal microautophagy (eMI), cytoplasmic proteins are engulfed into late endosomes in an ESCRT machinery-dependent manner. eMI can be KFERQ-specific or occur in bulk and be induced by prolonged starvation. Its physiological regulation and function, however, are not understood. Here, we show that eMI in the Drosophila fat body, akin to the mammalian liver, is induced upon oxidative or genotoxic stress in an ESCRT and partially Hsc70-4-dependent manner. Interestingly, eMI activation is selective, as ER stress fails to elicit a response. Intriguingly, we find that reducing MA leads to a compensatory enhancement of eMI, suggesting a tight interplay between these degradative processes. Furthermore, we show that mutations in DNA damage response genes are sufficient to trigger eMI and that the response to oxidative stress is under the control of MAPK/JNK signaling. Our data suggest that, controlled by various signaling pathways, eMI allows an organ to react and adapt to specific types of stress and is thus likely critical to prevent disease. Abbreviations: Atg: autophagy-related; CMA: chaperone-mediated autophagy; DDR: DNA damage repair; Df: deficiency (deletion); (E)GFP: (enhanced) green fluorescent protein; eMI: endosomal microautophagy; ER: endoplasmatic reticulum; ESCRT: endosomal sorting complexes required for transport; Eto: etoposide; FLP: flipase; Hsc: heat shock cognate protein; LAMP2A: lysosomal-associated membrane protein 2A; LE: late endosome; MA: macroautophagy; MI: microautophagy; MVB: multivesicular body; PA: photoactivatable; Para: paraquat; ROS: reactive oxygen species; SEM: standard error of means; Tor: target of rapamycin [serine/threonine kinase]; UPR: unfolded protein response; Vps: vacuolar protein sorting.
KW - Autophagy
KW - DNA damage
KW - ER stress
KW - ROS
KW - microautophagy
KW - oxidative stress
KW - proteostasis
UR - http://www.scopus.com/inward/record.url?scp=85087894299&partnerID=8YFLogxK
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U2 - 10.1080/15548627.2020.1783833
DO - 10.1080/15548627.2020.1783833
M3 - Article
C2 - 32559125
AN - SCOPUS:85087894299
SP - 1
EP - 13
JO - Autophagy
JF - Autophagy
SN - 1554-8627
ER -