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Title

Hypertonic stress promotes autophagy and microtubule-dependent autophagosomal clusters

Authors
Roth, Isabelle
Bouley, Richard
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Published in Autophagy. 2013, vol. 9, no. 4, p. 550-67
Abstract Osmotic homeostasis is fundamental for most cells, which face recurrent alterations of environmental osmolality that challenge cell viability. Protein damage is a consequence of hypertonic stress, but whether autophagy contributes to the osmoprotective response is unknown. Here, we investigated the possible implications of autophagy and microtubule organization on the response to hypertonic stress. We show that hypertonicity rapidly induced long-lived protein degradation, LC3-II generation and Ptdlns3K-dependent formation of LC3- and ATG12-positive puncta. Lysosomotropic agents chloroquine and bafilomycin A 1, but not nutrient deprivation or rapamycin treatment, further increased LC3-II generation, as well as ATG12-positive puncta, indicating that hypertonic stress increases autophagic flux. Autophagy induction upon hypertonic stress enhanced cell survival since cell death was increased by ATG12 siRNA-mediated knockdown and reduced by rapamycin. We additionally showed that hypertonicity induces fast reorganization of microtubule networks, which is associated with strong reorganization of microtubules at centrosomes and fragmentation of Golgi ribbons. Microtubule remodeling was associated with pericentrosomal clustering of ATG12-positive autolysosomes that colocalized with SQSTM1/p62 and ubiquitin, indicating that autophagy induced by hypertonic stress is at least partly selective. Efficient autophagy by hypertonic stress required microtubule remodeling and was DYNC/dynein-dependent as autophagosome clustering was enhanced by paclitaxel-induced microtubule stabilization and was reduced by nocodazole-induced tubulin depolymerization as well as chemical (EHNA) or genetic [DCTN2/dynactin 2 (p50) overexpression] interference of DYNC activity. The data document a general and hitherto overlooked mechanism, where autophagy and microtubule remodeling play prominent roles in the osmoprotective response.
Keywords Adaptor Proteins, Signal Transducing/metabolismAnimalsAutophagy/drug effectsCell Nucleus/drug effects/metabolismCell Survival/drug effectsDyneins/metabolismHumansHypertonic Solutions/pharmacologyLLC-PK1 CellsLysosomes/drug effects/metabolismMicrotubule-Associated Proteins/metabolismMicrotubules/drug effects/metabolismPhagosomes/drug effects/metabolismStress, Physiological/drug effectsSwine
Identifiers
PMID: 23380587
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Structures
Research groups Groupe Eric Féraille (néphrologie) (29)
Signaux intracellulaires (210)
Obésité et syndrome métabolique (803)
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NUNES-HASLER, Paula et al. Hypertonic stress promotes autophagy and microtubule-dependent autophagosomal clusters. In: Autophagy, 2013, vol. 9, n° 4, p. 550-67. https://archive-ouverte.unige.ch/unige:33350

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Deposited on : 2014-01-16

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