Avian reovirus p17 and σA act cooperatively to downregulate Akt by suppressing mTORC2 and CDK2/cyclin A2 and upregulating proteasome PSMB6
Abstract Although we have shown that avian reovirus (ARV) p17-mediated inhibition of Akt leads to induction of autophagy, the precise mechanisms remain largely unknown. This study has identified a specific mechanism by which ARV coordinately regulates the degradation of ribosomal proteins by p17-med...
Main Authors: | , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Nature Publishing Group
2017-07-01
|
Series: | Scientific Reports |
Online Access: | https://doi.org/10.1038/s41598-017-05510-x |
id |
doaj-0f15e8c5b9164b95ac8d3b6b24d492eb |
---|---|
record_format |
Article |
spelling |
doaj-0f15e8c5b9164b95ac8d3b6b24d492eb2020-12-08T00:38:36ZengNature Publishing GroupScientific Reports2045-23222017-07-017111910.1038/s41598-017-05510-xAvian reovirus p17 and σA act cooperatively to downregulate Akt by suppressing mTORC2 and CDK2/cyclin A2 and upregulating proteasome PSMB6Wei-Ru Huang0Pei-I Chi1Hung-Chuan Chiu2Jue-Liang Hsu3Brent L. Nielsen4Tsai-Ling Liao5Hung-Jen Liu6Institute of Molecular Biology, National Chung Hsing UniversityInstitute of Molecular Biology, National Chung Hsing UniversityInstitute of Molecular Biology, National Chung Hsing UniversityDepartment of Biological Science and Technology, National Pingtung University of Science and TechnologyDepartment of Microbiology and Molecular Biology, Brigham Young UniversityRong Hsing Research Center for Translational Medicine, National Chung Hsing UniversityInstitute of Molecular Biology, National Chung Hsing UniversityAbstract Although we have shown that avian reovirus (ARV) p17-mediated inhibition of Akt leads to induction of autophagy, the precise mechanisms remain largely unknown. This study has identified a specific mechanism by which ARV coordinately regulates the degradation of ribosomal proteins by p17-mediated activation of E3 ligase MDM2 that targets ribosomal proteins and by σA-mediated upregulation of proteasome PSMB6. In addition to downregulating ribosomal proteins, p17 reduces mTORC2 assembly and disrupts mTORC2-robosome association, both of which inactivate mTORC2 leading to inhibition of Akt phosphorylation at S473. Furthermore, we discovered that p17 binds to and inhibits the CDK2/cyclin A2 complex, further inhibiting phosphorylation of Akt S473. The negative effect of p17 on mTORC2 assembly and Akt phosphorylation at S473 is reversed in cells treated with insulin or overexpression of CDK2. The carboxyl terminus of p17 is necessary for interaction with CDK2 and for induction of autophagy. Furthermore, p17-mediated upregulation of LC3-II could be partially reversed by overexpression of CDK2. The present study provides mechanistic insights into cooperation between p17 and σA proteins of ARV to negatively regulate Akt by downregulating complexes of mTORC2 and CDK2/cyclin A2 and upregulating PSMB6, which together induces autophagy and cell cycle arrest and benefits virus replication.https://doi.org/10.1038/s41598-017-05510-x |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Wei-Ru Huang Pei-I Chi Hung-Chuan Chiu Jue-Liang Hsu Brent L. Nielsen Tsai-Ling Liao Hung-Jen Liu |
spellingShingle |
Wei-Ru Huang Pei-I Chi Hung-Chuan Chiu Jue-Liang Hsu Brent L. Nielsen Tsai-Ling Liao Hung-Jen Liu Avian reovirus p17 and σA act cooperatively to downregulate Akt by suppressing mTORC2 and CDK2/cyclin A2 and upregulating proteasome PSMB6 Scientific Reports |
author_facet |
Wei-Ru Huang Pei-I Chi Hung-Chuan Chiu Jue-Liang Hsu Brent L. Nielsen Tsai-Ling Liao Hung-Jen Liu |
author_sort |
Wei-Ru Huang |
title |
Avian reovirus p17 and σA act cooperatively to downregulate Akt by suppressing mTORC2 and CDK2/cyclin A2 and upregulating proteasome PSMB6 |
title_short |
Avian reovirus p17 and σA act cooperatively to downregulate Akt by suppressing mTORC2 and CDK2/cyclin A2 and upregulating proteasome PSMB6 |
title_full |
Avian reovirus p17 and σA act cooperatively to downregulate Akt by suppressing mTORC2 and CDK2/cyclin A2 and upregulating proteasome PSMB6 |
title_fullStr |
Avian reovirus p17 and σA act cooperatively to downregulate Akt by suppressing mTORC2 and CDK2/cyclin A2 and upregulating proteasome PSMB6 |
title_full_unstemmed |
Avian reovirus p17 and σA act cooperatively to downregulate Akt by suppressing mTORC2 and CDK2/cyclin A2 and upregulating proteasome PSMB6 |
title_sort |
avian reovirus p17 and σa act cooperatively to downregulate akt by suppressing mtorc2 and cdk2/cyclin a2 and upregulating proteasome psmb6 |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2017-07-01 |
description |
Abstract Although we have shown that avian reovirus (ARV) p17-mediated inhibition of Akt leads to induction of autophagy, the precise mechanisms remain largely unknown. This study has identified a specific mechanism by which ARV coordinately regulates the degradation of ribosomal proteins by p17-mediated activation of E3 ligase MDM2 that targets ribosomal proteins and by σA-mediated upregulation of proteasome PSMB6. In addition to downregulating ribosomal proteins, p17 reduces mTORC2 assembly and disrupts mTORC2-robosome association, both of which inactivate mTORC2 leading to inhibition of Akt phosphorylation at S473. Furthermore, we discovered that p17 binds to and inhibits the CDK2/cyclin A2 complex, further inhibiting phosphorylation of Akt S473. The negative effect of p17 on mTORC2 assembly and Akt phosphorylation at S473 is reversed in cells treated with insulin or overexpression of CDK2. The carboxyl terminus of p17 is necessary for interaction with CDK2 and for induction of autophagy. Furthermore, p17-mediated upregulation of LC3-II could be partially reversed by overexpression of CDK2. The present study provides mechanistic insights into cooperation between p17 and σA proteins of ARV to negatively regulate Akt by downregulating complexes of mTORC2 and CDK2/cyclin A2 and upregulating PSMB6, which together induces autophagy and cell cycle arrest and benefits virus replication. |
url |
https://doi.org/10.1038/s41598-017-05510-x |
work_keys_str_mv |
AT weiruhuang avianreovirusp17andsaactcooperativelytodownregulateaktbysuppressingmtorc2andcdk2cyclina2andupregulatingproteasomepsmb6 AT peiichi avianreovirusp17andsaactcooperativelytodownregulateaktbysuppressingmtorc2andcdk2cyclina2andupregulatingproteasomepsmb6 AT hungchuanchiu avianreovirusp17andsaactcooperativelytodownregulateaktbysuppressingmtorc2andcdk2cyclina2andupregulatingproteasomepsmb6 AT juelianghsu avianreovirusp17andsaactcooperativelytodownregulateaktbysuppressingmtorc2andcdk2cyclina2andupregulatingproteasomepsmb6 AT brentlnielsen avianreovirusp17andsaactcooperativelytodownregulateaktbysuppressingmtorc2andcdk2cyclina2andupregulatingproteasomepsmb6 AT tsailingliao avianreovirusp17andsaactcooperativelytodownregulateaktbysuppressingmtorc2andcdk2cyclina2andupregulatingproteasomepsmb6 AT hungjenliu avianreovirusp17andsaactcooperativelytodownregulateaktbysuppressingmtorc2andcdk2cyclina2andupregulatingproteasomepsmb6 |
_version_ |
1724396043473256448 |