The transcription factor MYC regulates cell survival and growth, and its level is tightly controlled in normal cells. We report that serine pyrophosphorylation — a posttranslational modification triggered by inositol pyrophosphate signaling molecules — controls MYC levels via regulated protein degradation. We find that endogenous MYC is stabilized and less polyubiquitinated in cells with reduced inositol pyrophosphates. We show that the inositol pyrophosphate 5-IP7 transfers its high-energy beta phosphate moiety to pre-phosphorylated serine residues in the central PEST domain of MYC. Loss of serine pyrophosphorylation in the PEST domain lowers the extent of MYC polyubiquitination and increases its stability. Fusion to the MYC PEST domain lowers the stability of GFP, but this effect is dependent on the extent of PEST domain pyrophosphorylation. The E3 ubiquitin ligase FBW7 can bind directly to the PEST domain of MYC, and this interaction is exclusively dependent on serine pyrophosphorylation. A stabilized, pyrophosphorylation-deficient form of MYC increases cell death during growth stress in untransformed cells. Splenocytes from mice lacking IP6K1, a kinase responsible for the synthesis of 5-IP7, have higher levels of MYC, and show increased cell proliferation in response to mitogens, compared with splenocytes from wild type mice. Thus, control of MYC stability through a novel pyro-phosphodegron provides unexpected insight into the regulation of cell survival in response to environmental cues.
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April 2021
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Serine pyrophosphorylation by the inositol pyrophosphate 5-IP7 keeps cellular MYC levels in check. Elevation in MYC downstream to 5-IP7 depletion influences cell fate in response to environmental cues. For further information see the article in this issue by Lolla and colleagues (pp. 1647–1661). Image was created by Akruti Shah using BioRender.
Research Article|
April 30 2021
Inositol pyrophosphates promote MYC polyubiquitination by FBW7 to regulate cell survival
Padmavathi Lolla;
Padmavathi Lolla
*
Conceptualization, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft, Writing - review & editing
1Laboratory of Cell Signalling, Centre for DNA Fingerprinting and Diagnostics (CDFD), Inner Ring Road, Uppal, Hyderabad 500039, India
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Akruti Shah;
Akruti Shah
*
Conceptualization, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft, Writing - review & editing
1Laboratory of Cell Signalling, Centre for DNA Fingerprinting and Diagnostics (CDFD), Inner Ring Road, Uppal, Hyderabad 500039, India
2Graduate Studies, Manipal Academy of Higher Education, Manipal 576104, India
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C.P. Unnikannan;
C.P. Unnikannan
†
1Laboratory of Cell Signalling, Centre for DNA Fingerprinting and Diagnostics (CDFD), Inner Ring Road, Uppal, Hyderabad 500039, India
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Vineesha Oddi;
Vineesha Oddi
‡
Investigation
1Laboratory of Cell Signalling, Centre for DNA Fingerprinting and Diagnostics (CDFD), Inner Ring Road, Uppal, Hyderabad 500039, India
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Rashna Bhandari
Conceptualization, Formal analysis, Supervision, Funding acquisition, Validation, Writing - original draft, Project administration, Writing - review & editing
1Laboratory of Cell Signalling, Centre for DNA Fingerprinting and Diagnostics (CDFD), Inner Ring Road, Uppal, Hyderabad 500039, India
Correspondence: Rashna Bhandari (rashna@cdfd.org.in)
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Publisher: Portland Press Ltd
Received:
February 09 2021
Revision Received:
March 26 2021
Accepted:
April 06 2021
Accepted Manuscript online:
April 06 2021
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2021
Biochem J (2021) 478 (8): 1647–1661.
Article history
Received:
February 09 2021
Revision Received:
March 26 2021
Accepted:
April 06 2021
Accepted Manuscript online:
April 06 2021
Citation
Padmavathi Lolla, Akruti Shah, C.P. Unnikannan, Vineesha Oddi, Rashna Bhandari; Inositol pyrophosphates promote MYC polyubiquitination by FBW7 to regulate cell survival. Biochem J 30 April 2021; 478 (8): 1647–1661. doi: https://doi.org/10.1042/BCJ20210081
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