Activation of autophagy depends on Atg1/Ulk1-mediated phosphorylation and inhibition of the Hsp90 chaperone machinery
Summary: Cellular homeostasis relies on both the chaperoning of proteins and the intracellular degradation system that delivers cytoplasmic constituents to the lysosome, a process known as autophagy. The crosstalk between these processes and their underlying regulatory mechanisms is poorly understoo...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-07-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723008185 |
| _version_ | 1797780009798074368 |
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| author | Sarah J. Backe Rebecca A. Sager Jennifer A. Heritz Laura A. Wengert Katherine A. Meluni Xavier Aran-Guiu Barry Panaretou Mark R. Woodford Chrisostomos Prodromou Dimitra Bourboulia Mehdi Mollapour |
| author_facet | Sarah J. Backe Rebecca A. Sager Jennifer A. Heritz Laura A. Wengert Katherine A. Meluni Xavier Aran-Guiu Barry Panaretou Mark R. Woodford Chrisostomos Prodromou Dimitra Bourboulia Mehdi Mollapour |
| author_sort | Sarah J. Backe |
| collection | DOAJ |
| description | Summary: Cellular homeostasis relies on both the chaperoning of proteins and the intracellular degradation system that delivers cytoplasmic constituents to the lysosome, a process known as autophagy. The crosstalk between these processes and their underlying regulatory mechanisms is poorly understood. Here, we show that the molecular chaperone heat shock protein 90 (Hsp90) forms a complex with the autophagy-initiating kinase Atg1 (yeast)/Ulk1 (mammalian), which suppresses its kinase activity. Conversely, environmental cues lead to Atg1/Ulk1-mediated phosphorylation of a conserved serine in the amino domain of Hsp90, inhibiting its ATPase activity and altering the chaperone dynamics. These events impact a conformotypic peptide adjacent to the activation and catalytic loop of Atg1/Ulk1. Finally, Atg1/Ulk1-mediated phosphorylation of Hsp90 leads to dissociation of the Hsp90:Atg1/Ulk1 complex and activation of Atg1/Ulk1, which is essential for initiation of autophagy. Our work indicates a reciprocal regulatory mechanism between the chaperone Hsp90 and the autophagy kinase Atg1/Ulk1 and consequent maintenance of cellular proteostasis. |
| first_indexed | 2024-03-12T23:38:35Z |
| format | Article |
| id | doaj.art-4372f2b85d70407f912e42e25ea43467 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-12T23:38:35Z |
| publishDate | 2023-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-4372f2b85d70407f912e42e25ea434672023-07-15T04:28:36ZengElsevierCell Reports2211-12472023-07-01427112807Activation of autophagy depends on Atg1/Ulk1-mediated phosphorylation and inhibition of the Hsp90 chaperone machinerySarah J. Backe0Rebecca A. Sager1Jennifer A. Heritz2Laura A. Wengert3Katherine A. Meluni4Xavier Aran-Guiu5Barry Panaretou6Mark R. Woodford7Chrisostomos Prodromou8Dimitra Bourboulia9Mehdi Mollapour10Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USADepartment of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USADepartment of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USADepartment of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USADepartment of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USABiochemistry and Biomedicine, School of Life Sciences, University of Sussex, Brighton, UKSchool of Cancer and Pharmaceutical Sciences, Institute of Pharmaceutical Science, King’s College London, London SE1 9NQ, UKDepartment of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USAGenome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UKDepartment of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USADepartment of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Corresponding authorSummary: Cellular homeostasis relies on both the chaperoning of proteins and the intracellular degradation system that delivers cytoplasmic constituents to the lysosome, a process known as autophagy. The crosstalk between these processes and their underlying regulatory mechanisms is poorly understood. Here, we show that the molecular chaperone heat shock protein 90 (Hsp90) forms a complex with the autophagy-initiating kinase Atg1 (yeast)/Ulk1 (mammalian), which suppresses its kinase activity. Conversely, environmental cues lead to Atg1/Ulk1-mediated phosphorylation of a conserved serine in the amino domain of Hsp90, inhibiting its ATPase activity and altering the chaperone dynamics. These events impact a conformotypic peptide adjacent to the activation and catalytic loop of Atg1/Ulk1. Finally, Atg1/Ulk1-mediated phosphorylation of Hsp90 leads to dissociation of the Hsp90:Atg1/Ulk1 complex and activation of Atg1/Ulk1, which is essential for initiation of autophagy. Our work indicates a reciprocal regulatory mechanism between the chaperone Hsp90 and the autophagy kinase Atg1/Ulk1 and consequent maintenance of cellular proteostasis.http://www.sciencedirect.com/science/article/pii/S2211124723008185CP: Molecular biology |
| spellingShingle | Sarah J. Backe Rebecca A. Sager Jennifer A. Heritz Laura A. Wengert Katherine A. Meluni Xavier Aran-Guiu Barry Panaretou Mark R. Woodford Chrisostomos Prodromou Dimitra Bourboulia Mehdi Mollapour Activation of autophagy depends on Atg1/Ulk1-mediated phosphorylation and inhibition of the Hsp90 chaperone machinery Cell Reports CP: Molecular biology |
| title | Activation of autophagy depends on Atg1/Ulk1-mediated phosphorylation and inhibition of the Hsp90 chaperone machinery |
| title_full | Activation of autophagy depends on Atg1/Ulk1-mediated phosphorylation and inhibition of the Hsp90 chaperone machinery |
| title_fullStr | Activation of autophagy depends on Atg1/Ulk1-mediated phosphorylation and inhibition of the Hsp90 chaperone machinery |
| title_full_unstemmed | Activation of autophagy depends on Atg1/Ulk1-mediated phosphorylation and inhibition of the Hsp90 chaperone machinery |
| title_short | Activation of autophagy depends on Atg1/Ulk1-mediated phosphorylation and inhibition of the Hsp90 chaperone machinery |
| title_sort | activation of autophagy depends on atg1 ulk1 mediated phosphorylation and inhibition of the hsp90 chaperone machinery |
| topic | CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723008185 |
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