Circadian E3 ligase FBXL21 regulates daily muscle proteostasis by targeting DNAJB6
Loss of FBXL21 disrupts client protein degradation, worsening stress responses in muscle cells and mutant mice.
In mouse muscle cells and mice, researchers investigated how the circadian E3 ligase FBXL21 controls daily proteostasis. They found that FBXL21 promotes the proteasomal degradation of the co-chaperone DNAJB6 and its client proteins, including Desmin. Myopathy-causing DNAJB6 mutations resisted this degradation. In Fbxl21 knockout C2C12 cells, Desmin accumulated abnormally, and heat shock aggravated cytoplasmic buildup of the client protein TDP-43. In wild-type mice, timed exercise generated daily rhythms in TDP-43 and the stress granule markers G3BP1 and FUS. In contrast, Fbxl21 hypomorphic mice showed elevated levels of these markers at baseline and under exercise-induced stress. Restoring skeletal muscle-specific FBXL21 expression successfully rescued these protein abnormalities in mice.
Why it matters
Maintaining diurnal proteostasis is critical to preserving skeletal muscle function under physiological stress. Understanding the FBXL21-DNAJB6 pathway reveals how circadian mechanisms help manage protein turnover and could inform therapies for muscle disorders.
Caveats
The experiments were conducted in cell culture and mouse models, so findings may not directly translate to human physiology. Additionally, the study relied on genetic knockout and hypomorphic models rather than testing interventions across natural aging.
- Exercise
- FBXL21 knockout
- FBXL21 overexpression
- Loss of proteostasis
- Circadian clock
- Heat shock response and chaperones
- Ubiquitin–proteasome system
- Des
- Dnajb6
- Fbxl21
- Fus
- G3bp1
The paper
FBXL21 regulates diurnal proteostasis in skeletal muscle by targeting DNAJB6 and client proteins
Lim JY, Wi J, Wirianto M et al.
EMBO Reports · 30 Sep 2026