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ATF4 links ER stress with reticulophagy in glioblastoma cells

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  • Svenja Zielke, Univ Hosp Frankfurt, Goethe University Frankfurt, Goethe University Frankfurt Hospital
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  • Simon Kardo, Univ Hosp Frankfurt, Goethe University Frankfurt, Goethe University Frankfurt Hospital
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  • Laura Zein, Univ Hosp Frankfurt, Goethe University Frankfurt, Goethe University Frankfurt Hospital
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  • Muriel Mari
  • Adriana Covarrubias-Pinto, From the Danish Multiple Sclerosis Center (M.D.B., T.A.C., F.S., P.S.S., M.M.), Rigshospitalet; Copenhagen University Hospital Rigshospitalet (J.F., H.H.-K.-R.), Glostrup; Slagelse Hospital (M.K.G.); Odense University Hospital (Z.I., T.S.), University of Southern Denmark; Hospital of Southern Jutland (M.K.), Sønderborg; Aalborg University Hospital (Z.M.); Aarhus University Hospital (T.P., P.V.R.); Greater Copenhagen Hospitals-NOH (H.R.), Hillerød; University Hospital of Sjaelland (A.T.), Roskilde; and Depar
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  • Maximilian N Kinzler, Univ Hosp Frankfurt, Goethe University Frankfurt, Goethe University Frankfurt Hospital
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  • Nina Meyer, Univ Hosp Frankfurt, Goethe University Frankfurt, Goethe University Frankfurt Hospital
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  • Alexandra Stolz, From the Danish Multiple Sclerosis Center (M.D.B., T.A.C., F.S., P.S.S., M.M.), Rigshospitalet; Copenhagen University Hospital Rigshospitalet (J.F., H.H.-K.-R.), Glostrup; Slagelse Hospital (M.K.G.); Odense University Hospital (Z.I., T.S.), University of Southern Denmark; Hospital of Southern Jutland (M.K.), Sønderborg; Aalborg University Hospital (Z.M.); Aarhus University Hospital (T.P., P.V.R.); Greater Copenhagen Hospitals-NOH (H.R.), Hillerød; University Hospital of Sjaelland (A.T.), Roskilde; and Depar
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  • Simone Fulda, Univ Hosp Frankfurt, Goethe University Frankfurt, Goethe University Frankfurt Hospital
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  • Fulvio Reggiori
  • Donat Kögel, German Cancer Consortium (DKTK)
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  • Sjoerd van Wijk, Univ Hosp Frankfurt, Goethe University Frankfurt, Goethe University Frankfurt Hospital

Selective degradation of the endoplasmic reticulum (ER; reticulophagy) is a type of autophagy involved in the removal of ER fragments. So far, amino acid starvation as well as ER stress have been described as inducers of reticulophagy, which in turn restores cellular energy levels and ER homeostasis. Here, we explored the autophagy-inducing mechanisms that underlie the autophagic cell death (ACD)-triggering compound loperamide (LOP) in glioblastoma cells. Interestingly, LOP triggers upregulation of the transcription factor ATF4, which is accompanied by the induction of additional ER stress markers. Notably, knockout of ATF4 significantly attenuated LOP-induced autophagy and ACD. Functionally, LOP also specifically induces the engulfment of large ER fragments within autophagosomes and lysosomes as determined by electron and fluorescence microscopy. LOP-induced reticulophagy and cell death are predominantly mediated through the reticulophagy receptor RETREG1/FAM134B and, to a lesser extent, TEX264, confirming that reticulophagy receptors can promote ACD. Strikingly, apart from triggering LOP-induced autophagy and ACD, ATF4 is also required for LOP-induced reticulophagy. These observations highlight a key role for ATF4, RETREG1 and TEX264 in response to LOP-induced ER stress, reticulophagy and ACD, and establish a novel mechanistic link between ER stress and reticulophagy, with possible implications for additional models of drug-induced ER stress.Abbreviations: ACD: autophagic cell death; ATF6: activating transcription factor 6; ATL3: atlastin 3; BafA1: bafilomycin A1; CCPG1: cell cycle progression gene 1; co-IP: co-immunoprecipitation; DDIT3/CHOP: DNA damage inducible transcript 3; ER: endoplasmic reticulum; EIF2A/eIF2α: eukaryotic translation initiation factor 2A; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; ERN1/IRE1α: endoplasmic reticulum to nucleus signaling 1; GABARAP: GABA type A receptor-associated protein; GBM: glioblastoma multiforme; HSPA5/BiP: heat shock protein family (Hsp70) member 5; LOP: loperamide; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; RETREG1/FAM134B: reticulophagy regulator 1; RTN3L: reticulon 3 long; SEC62: SEC62 homolog, protein translocation factor; TEX264: testis-expressed 264, reticulophagy receptor; UPR: unfolded protein response.

Original languageEnglish
JournalAutophagy
Volume17
Issue9
Pages (from-to)2432-2448
Number of pages17
ISSN1554-8627
DOIs
Publication statusPublished - Sep 2021

    Research areas

  • Activating Transcription Factor 4/metabolism, Autophagy/physiology, Endoplasmic Reticulum Stress, Endoribonucleases/metabolism, Glioblastoma/pathology, Humans, Protein Serine-Threonine Kinases

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