Abstract
Cullin-RING ligases (CRLs) are central regulators of environmental and cellular stress responses, orchestrating diverse processes through the ubiquitination of substrate proteins. As modular complexes, CRLs employ substrate-specific adaptors to target proteins for degradation and other ubiquitin-mediated processes, enabling dynamic adaptation to environmental cues. Recent advances have highlighted the largest CRL subfamily SCF (Skp1-cullin-F-box) in environmental sensing, a role historically underappreciated for SCF ubiquitin ligases. Notably, emerging evidence suggests that the F-box domain, a 50-amino acid motif traditionally recognized for mediating protein-protein interactions, can act as a direct environmental sensor due to its ability to bind heavy metals. Despite these advances, the roles of many CRL components in environmental sensing remain poorly understood. This review provides an overview of CRLs in stress response regulation and emphasizes the emerging functions of F-box proteins in environmental adaptation.