2. Academic Validation
  3. Nuclear p62/SQSTM1 facilitates ubiquitin-independent proteasomal degradation of BMAL1

Nuclear p62/SQSTM1 facilitates ubiquitin-independent proteasomal degradation of BMAL1

  • PLoS Genet. 2025 Jul 10;21(7):e1011794. doi: 10.1371/journal.pgen.1011794.
Chenliang Zhang 1,  Quanyou Wu 2,  Huan Zhang 3,  Ruichen Liu 4,  Liping Li 5
Affiliations

Affiliations

  • 1 Division of Abdominal Tumor Multimodality Treatment, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
  • 2 Division of Abdominal Tumor Multimodality Treatment, Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
  • 3 Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
  • 4 West China School of Medicine, Sichuan University, Chengdu, Sichuan Province, China.
  • 5 Department of Pharmacy, Chengdu Fifth People's Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China.
PMID: 40638681 DOI: 10.1371/journal.pgen.1011794
Abstract

Brain and muscle arnt-like protein 1(BMAL1) is a critical regulator of circadian rhythm. Although transcriptional regulation of BMAL1 has been extensively studied, the mechanisms governing the stability of BMAL1 at the protein level remain unclear. p62/SQSTM1 is a crucial factor in proteostasis regulation and is involved in both Autophagy and the ubiquitin-proteasome system. We demonstrated that p62 promotes proteasomal degradation of BMAL1 within the nucleus, independent of ubiquitination. Additional molecular analyses indicated that p62 functions as a receptor for the 20S Proteasome, facilitating the recruitment of BMAL1 to the 20S Proteasome for degradation. This mechanism is independent of recently identified p62-driven nuclear biomolecular condensates. We also revealed that remodeling the nuclear accumulation of p62 may represent a potential strategy for targeting BMAL1 to suppress tumor cell growth. In conclusion, our findings revealed a novel mechanism by which nuclear p62 regulates BMAL1 proteostasis.

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