AMPK-dependent activation of the Cyclin Y/CDK16 complex controls autophagy

Marc Dohmen; Sarah Krieg; Georgios Agalaridis; Xiaoqing Zhu; Saifeldin N. Shehata; Elisabeth Pfeiffenberger; Jan Amelang; Mareike Buetepage; Elena Buerova; Carolina M. Pfaff; Dipanjan Chanda; Stephan Geley; Christian Preisinger; Kei Sakamoto; Bernhard Lüscher; Dietbert Neumann; Joerg Vervoorts

doi:10.1038/s41467-020-14812-0

AMPK-dependent activation of the Cyclin Y/CDK16 complex controls autophagy

Marc Dohmen, Sarah Krieg, Georgios Agalaridis, Xiaoqing Zhu, Saifeldin N. Shehata, Elisabeth Pfeiffenberger, Jan Amelang, Mareike Buetepage, Elena Buerova, Carolina M. Pfaff, Dipanjan Chanda, Stephan Geley, Christian Preisinger, Kei Sakamoto, Bernhard Lüscher^*, Dietbert Neumann^*, Joerg Vervoorts^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

The AMP-activated protein kinase (AMPK) is a master sensor of the cellular energy status that is crucial for the adaptive response to limited energy availability. AMPK is implicated in the regulation of many cellular processes, including autophagy. However, the precise mechanisms by which AMPK controls these processes and the identities of relevant substrates are not fully understood. Using protein microarrays, we identify Cyclin Y as an AMPK substrate that is phosphorylated at Serine 326 (S326) both in vitro and in cells. Phosphorylation of Cyclin Y at S326 promotes its interaction with the Cyclin-dependent kinase 16 (CDK16), thereby stimulating its catalytic activity. When expressed in cells, Cyclin Y/CDK16 is sufficient to promote autophagy. Moreover, Cyclin Y/CDK16 is necessary for efficient AMPK-dependent activation of autophagy. This functional interaction is mediated by AMPK phosphorylating S326 of Cyclin Y. Collectively, we define Cyclin Y/CDK16 as downstream effector of AMPK for inducing autophagy.

Original language	English
Article number	1032
Number of pages	18
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-14812-0
Publication status	Published - 25 Feb 2020

Keywords

PROTEIN-KINASE
COMPUTATIONAL PLATFORM
PHOSPHORYLATION SITES
REGULATE AUTOPHAGY
CELLULAR AMPK
ENERGY
PATHWAYS
NUTRIENT
IDENTIFICATION
A-769662

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Dohmen, M., Krieg, S., Agalaridis, G., Zhu, X., Shehata, S. N., Pfeiffenberger, E., Amelang, J., Buetepage, M., Buerova, E., Pfaff, C. M., Chanda, D., Geley, S., Preisinger, C., Sakamoto, K., Lüscher, B., Neumann, D., & Vervoorts, J. (2020). AMPK-dependent activation of the Cyclin Y/CDK16 complex controls autophagy. Nature Communications, 11(1), Article 1032. https://doi.org/10.1038/s41467-020-14812-0

@article{30cd9fcb7e4541928a867f79afb73cda,

title = "AMPK-dependent activation of the Cyclin Y/CDK16 complex controls autophagy",

abstract = "The AMP-activated protein kinase (AMPK) is a master sensor of the cellular energy status that is crucial for the adaptive response to limited energy availability. AMPK is implicated in the regulation of many cellular processes, including autophagy. However, the precise mechanisms by which AMPK controls these processes and the identities of relevant substrates are not fully understood. Using protein microarrays, we identify Cyclin Y as an AMPK substrate that is phosphorylated at Serine 326 (S326) both in vitro and in cells. Phosphorylation of Cyclin Y at S326 promotes its interaction with the Cyclin-dependent kinase 16 (CDK16), thereby stimulating its catalytic activity. When expressed in cells, Cyclin Y/CDK16 is sufficient to promote autophagy. Moreover, Cyclin Y/CDK16 is necessary for efficient AMPK-dependent activation of autophagy. This functional interaction is mediated by AMPK phosphorylating S326 of Cyclin Y. Collectively, we define Cyclin Y/CDK16 as downstream effector of AMPK for inducing autophagy.",

keywords = "PROTEIN-KINASE, COMPUTATIONAL PLATFORM, PHOSPHORYLATION SITES, REGULATE AUTOPHAGY, CELLULAR AMPK, ENERGY, PATHWAYS, NUTRIENT, IDENTIFICATION, A-769662",

author = "Marc Dohmen and Sarah Krieg and Georgios Agalaridis and Xiaoqing Zhu and Shehata, {Saifeldin N.} and Elisabeth Pfeiffenberger and Jan Amelang and Mareike Buetepage and Elena Buerova and Pfaff, {Carolina M.} and Dipanjan Chanda and Stephan Geley and Christian Preisinger and Kei Sakamoto and Bernhard L{\"u}scher and Dietbert Neumann and Joerg Vervoorts",

note = "Funding Information: We thank B. Lippok and J. Stahl for excellent technical assistance, A. Sechi for technical support and David Stephens, Stefano Ferrari, Terje Johansen, Trond Lamark and Martin Eilers for providing plasmids. The Confocal Microscopy Core Facility of the IZKF Aachen assisted our experiments. This work was supported by the START and IZKF programs of the Medical School of the RWTH Aachen University (J.V.), a VIDI-Innovational Research Grant from the Netherlands Organization of Scientific Research (NWO-ALW Grant no. 864.10.007; D.N), the Chinese Scholarship Council (X.Z.), and a Marie Curie fellowship (Grant PIIF-GA-2012-332230; D.C.), and a grant from the Deutsche Forschungsgemeinschaft (LU 466/16-2; B.L.). Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = feb,

day = "25",

doi = "10.1038/s41467-020-14812-0",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

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Dohmen, M, Krieg, S, Agalaridis, G, Zhu, X, Shehata, SN, Pfeiffenberger, E, Amelang, J, Buetepage, M, Buerova, E, Pfaff, CM, Chanda, D, Geley, S, Preisinger, C, Sakamoto, K, Lüscher, B, Neumann, D & Vervoorts, J 2020, 'AMPK-dependent activation of the Cyclin Y/CDK16 complex controls autophagy', Nature Communications, vol. 11, no. 1, 1032. https://doi.org/10.1038/s41467-020-14812-0

TY - JOUR

T1 - AMPK-dependent activation of the Cyclin Y/CDK16 complex controls autophagy

AU - Dohmen, Marc

AU - Krieg, Sarah

AU - Agalaridis, Georgios

AU - Zhu, Xiaoqing

AU - Shehata, Saifeldin N.

AU - Pfeiffenberger, Elisabeth

AU - Amelang, Jan

AU - Buetepage, Mareike

AU - Buerova, Elena

AU - Pfaff, Carolina M.

AU - Chanda, Dipanjan

AU - Geley, Stephan

AU - Preisinger, Christian

AU - Sakamoto, Kei

AU - Lüscher, Bernhard

AU - Neumann, Dietbert

AU - Vervoorts, Joerg

N1 - Funding Information: We thank B. Lippok and J. Stahl for excellent technical assistance, A. Sechi for technical support and David Stephens, Stefano Ferrari, Terje Johansen, Trond Lamark and Martin Eilers for providing plasmids. The Confocal Microscopy Core Facility of the IZKF Aachen assisted our experiments. This work was supported by the START and IZKF programs of the Medical School of the RWTH Aachen University (J.V.), a VIDI-Innovational Research Grant from the Netherlands Organization of Scientific Research (NWO-ALW Grant no. 864.10.007; D.N), the Chinese Scholarship Council (X.Z.), and a Marie Curie fellowship (Grant PIIF-GA-2012-332230; D.C.), and a grant from the Deutsche Forschungsgemeinschaft (LU 466/16-2; B.L.). Publisher Copyright: © 2020, The Author(s).

PY - 2020/2/25

Y1 - 2020/2/25

N2 - The AMP-activated protein kinase (AMPK) is a master sensor of the cellular energy status that is crucial for the adaptive response to limited energy availability. AMPK is implicated in the regulation of many cellular processes, including autophagy. However, the precise mechanisms by which AMPK controls these processes and the identities of relevant substrates are not fully understood. Using protein microarrays, we identify Cyclin Y as an AMPK substrate that is phosphorylated at Serine 326 (S326) both in vitro and in cells. Phosphorylation of Cyclin Y at S326 promotes its interaction with the Cyclin-dependent kinase 16 (CDK16), thereby stimulating its catalytic activity. When expressed in cells, Cyclin Y/CDK16 is sufficient to promote autophagy. Moreover, Cyclin Y/CDK16 is necessary for efficient AMPK-dependent activation of autophagy. This functional interaction is mediated by AMPK phosphorylating S326 of Cyclin Y. Collectively, we define Cyclin Y/CDK16 as downstream effector of AMPK for inducing autophagy.

AB - The AMP-activated protein kinase (AMPK) is a master sensor of the cellular energy status that is crucial for the adaptive response to limited energy availability. AMPK is implicated in the regulation of many cellular processes, including autophagy. However, the precise mechanisms by which AMPK controls these processes and the identities of relevant substrates are not fully understood. Using protein microarrays, we identify Cyclin Y as an AMPK substrate that is phosphorylated at Serine 326 (S326) both in vitro and in cells. Phosphorylation of Cyclin Y at S326 promotes its interaction with the Cyclin-dependent kinase 16 (CDK16), thereby stimulating its catalytic activity. When expressed in cells, Cyclin Y/CDK16 is sufficient to promote autophagy. Moreover, Cyclin Y/CDK16 is necessary for efficient AMPK-dependent activation of autophagy. This functional interaction is mediated by AMPK phosphorylating S326 of Cyclin Y. Collectively, we define Cyclin Y/CDK16 as downstream effector of AMPK for inducing autophagy.

KW - PROTEIN-KINASE

KW - COMPUTATIONAL PLATFORM

KW - PHOSPHORYLATION SITES

KW - REGULATE AUTOPHAGY

KW - CELLULAR AMPK

KW - ENERGY

KW - PATHWAYS

KW - NUTRIENT

KW - IDENTIFICATION

KW - A-769662

U2 - 10.1038/s41467-020-14812-0

DO - 10.1038/s41467-020-14812-0

M3 - Article

C2 - 32098961

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1032

ER -

AMPK-dependent activation of the Cyclin Y/CDK16 complex controls autophagy

Abstract

Keywords

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