2. Academic Validation
  3. USP8 and Hsp70 regulate endoreplication by synergistically promoting Fzr deubiquitination and stabilization

USP8 and Hsp70 regulate endoreplication by synergistically promoting Fzr deubiquitination and stabilization

  • Sci Adv. 2025 Mar 21;11(12):eadq9111. doi: 10.1126/sciadv.adq9111.
Wenliang Qian 1 2,  Xing Zhang 1 2,  Dongqin Yuan 1 2,  Yuting Wu 1 2,  Hao Li 1 2,  Ling Wei 3,  Zheng Li 1 2,  Zongcai Dai 1 2,  Pei Song 1 2,  Qiaoling Sun 1 2,  Zizhang Zhou 4,  Qingyou Xia 1 2,  Daojun Cheng 1 2
Affiliations

Affiliations

  • 1 Integrative Science Center of Germplasm Creation in Western China (CHONGQING) Science City, Biological Science Research Center, Southwest University, Chongqing 400715, China.
  • 2 State Key Laboratory of Resource Insects, Southwest University, Chongqing 400715, China.
  • 3 School of Life Sciences, Southwest University, Chongqing 400715, China.
  • 4 College of Life Sciences, Shandong Agricultural University, Tai'an 271018, China.
PMID: 40106570 DOI: 10.1126/sciadv.adq9111
Abstract

Endoreplication is characterized by multiple rounds of DNA replication without cell division and determines the growth and final size of endoreplicating cells and tissues in eukaryotes. The cyclic ubiquitination and degradation of several cell cycle regulators are required for endoreplication progression. However, the Deubiquitinase that deubiquitinates and stabilizes key factors to modulate endoreplication remains unknown. Here, we found in the endoreplicating Drosophila salivary gland and Bombyx silk gland that the depletion of ubiquitin-specific peptidase 8 (USP8) led to endoreplication arrest and a decrease in gland size. Mechanistically, we showed that USP8 interacted with the Fizzy-related (Fzr) protein, a conserved master regulator of endoreplication, thereby deubiquitinating and stabilizing Fzr to modulate endoreplication. Moreover, the molecular chaperone heat shock protein 70 (HSP70) mediated proper folding of Fzr and increased the interaction between Fzr and USP8, thereby promoting the deubiquitination and stabilization of Fzr. Together, our study demonstrates that USP8 and HSP70 regulate endoreplication by synergistically maintaining Fzr stability though deubiquitination.

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