Cyclin D-CDK4/6 couple proliferation to membrane and mitochondrial protein supply through a DeSI1 phospho-switch
- 1NYU GROSSMAN SCHOOL OF MEDICINE HHMI
Abstract
Cyclin D-CDK4/6 complexes drive cell-cycle entry through an RB-E2F-dependent transcriptional program, but how they coordinate proliferation with the membrane and organelle protein supply required for growth is unclear. We identify DeSI1 as a cyclin D-CDK4/6 substrate whose phosphorylation at S25 converts a latent homodimer into an active monomeric deubiquitylase that recognizes hydrophobic proteins such as those bearing transmembrane domains and mitochondrial targeting sequences. Phosphorylated DeSI1 extends the lifetime of newly synthesized hydrophobic proteins that support membrane and mitochondrial capacity. Constitutive DeSI1 activation uncouples this proteostatic program from metabolic supply, creating a cytidine-nucleotide supply-demand imbalance associated with impaired CTP-dependent phospholipid homeostasis, cardiolipin depletion, and mitochondrial decompensation - defects that cytidine reverses. In mice, constitutive DeSI1 activation causes progressive cerebellar degeneration with membrane-protein accumulation, respiratory-chain loss, and phospholipid depletion. These findings define a post-translational mechanism coupling cell-cycle entry to membrane and mitochondrial capacity, and reveal the cost of uncoupling this program from its metabolic support.
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BibTeX
@misc{kaisari2026cyclin,
title = {{Cyclin D-CDK4/6 couple proliferation to membrane and mitochondrial protein supply through a DeSI1 phospho-switch}},
author = {S. Kaisari and E. Lane and R. Wang and J. Estrada and M. Collu and D. Simoneschi and Y.-T. Jeong and M. Liu and Q. Zhang and Y. Kito and I. Abramovich and J. Yin and T. Rodrick and G. Ward and T. Cropley and A. Heguy and S. Y. Kim and R. Brosh and H. Wolosker and N. D. Udeshi and S. A. Carr and C. A. Loomis and F.-X. Liang and B. Ueberheide and D. Jones and N. Zheng and M. Pagano},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.16.752001},
url = {https://www.biorxiv.org/content/10.64898/2026.09.16.752001v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Cyclin D-CDK4/6 couple proliferation to membrane and mitochondrial protein supply through a DeSI1 phospho-switch
AU - S. Kaisari
AU - E. Lane
AU - R. Wang
AU - J. Estrada
AU - M. Collu
AU - D. Simoneschi
AU - Y.-T. Jeong
AU - M. Liu
AU - Q. Zhang
AU - Y. Kito
AU - I. Abramovich
AU - J. Yin
AU - T. Rodrick
AU - G. Ward
AU - T. Cropley
AU - A. Heguy
AU - S. Y. Kim
AU - R. Brosh
AU - H. Wolosker
AU - N. D. Udeshi
AU - S. A. Carr
AU - C. A. Loomis
AU - F.-X. Liang
AU - B. Ueberheide
AU - D. Jones
AU - N. Zheng
AU - M. Pagano
PY - 2026
DA - 2026/09/16
PB - bioRxiv
DO - 10.64898/2026.09.16.752001
UR - https://www.biorxiv.org/content/10.64898/2026.09.16.752001v1
AB - Cyclin D-CDK4/6 complexes drive cell-cycle entry through an RB-E2F-dependent transcriptional program, but how they coordinate proliferation with the membrane and organelle protein supply required for growth is unclear. We identify DeSI1 as a cyclin D-CDK4/6 substrate whose phosphorylation at S25 converts a latent homodimer into an active monomeric deubiquitylase that recognizes hydrophobic proteins such as those bearing transmembrane domains and mitochondrial targeting sequences. Phosphorylated DeSI1 extends the lifetime of newly synthesized hydrophobic proteins that support membrane and mitochondrial capacity. Constitutive DeSI1 activation uncouples this proteostatic program from metabolic supply, creating a cytidine-nucleotide supply-demand imbalance associated with impaired CTP-dependent phospholipid homeostasis, cardiolipin depletion, and mitochondrial decompensation - defects that cytidine reverses. In mice, constitutive DeSI1 activation causes progressive cerebellar degeneration with membrane-protein accumulation, respiratory-chain loss, and phospholipid depletion. These findings define a post-translational mechanism coupling cell-cycle entry to membrane and mitochondrial capacity, and reveal the cost of uncoupling this program from its metabolic support.
ER -