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

## TL;DR

This study reveals that p62/SQSTM1 helps degrade BMAL1, a key circadian rhythm protein, in the nucleus without needing ubiquitination or condensates.

## Contribution

The novel contribution is the discovery of a ubiquitin- and condensates-independent mechanism by which nuclear p62 regulates BMAL1 degradation.

## Key findings

- p62 promotes proteasomal degradation of BMAL1 in the nucleus without ubiquitination.
- p62 acts as a receptor linking BMAL1 to the 20S proteasome for degradation.
- Modulating nuclear p62 accumulation could suppress BMAL1-associated tumor growth.

## 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.

p62/SQSTM1 is a well-established regulator of protein quality control, playing a key role in the autophagic degradation of various proteins. Furthermore, studies have shown that p62 can promote the proteasomal degradation of ubiquitinated proteins. Recent research has highlighted that p62 drives the proteasomal degradation of nuclear proteins in a manner dependent on both ubiquitin and biomolecular condensates. In this study, we discovered that nuclear p62 promotes the proteasomal degradation of BMAL1, a critical regulator of the circadian rhythm, in a ubiquitin- and condensates-independent manner. Further analysis revealed that p62 acts as a bridge, linking BMAL1 to the 20S proteasome, thereby facilitating its proteasomal degradation. Additionally, we propose that modulating p62’s ability to accumulate in the nucleus could serve as a strategy to inhibit BMAL1-associated tumor proliferation. Our findings uncover a novel mechanism through which BMAL1 proteostasis is regulated by nuclear p62, shedding light on a new aspect of p62’s role in protein quality control.