Janitors at Work: The Multifaceted Role of the P97-UFD1-NPL4 Complex

The regulatory pathways governing protein homeostasis are a delicate balance of protein synthesis and degradation. At the core of proteolysis is a molecular "cleaning crew" composed of the P97 ATPase, ubiquitin fusion degradation 1 (UFD1), and nuclear protein localization 4 (NPL4). The ATPase activity of P97 drives the formation and activity of this complex, which is also regulated by post-translational modifications and ubiquitin regulatory X-domain proteins. Notably, the P97-UFD1-NPL4 complex plays a critical role in endoplasmic reticulum-associated degradation (ERAD), by retrotranslocating misfolded proteins from the endoplasmic reticulum (ER) to the cytosol. Beyond ERAD, this complex also targets proteins from mitochondria, ribosomes, and chromatin to regulate cellular processes such as organelle homeostasis, cell cycle progression, DNA replication, and DNA repair. The aberrant activity of the P97-UFD1-NPL4 complex can either accelerate or impair the removal of misfolded, unfolded, and regulatory proteins, disrupting cellular homeostasis and inducing various disorders. Significant efforts have been made to develop therapeutics that inhibit complex functions. However, to identify a suitable strategy, it is crucial to understand the molecular mechanisms linking the function of the complex to disease progression. In this review, we summarize the multifaceted roles of the P97-UFD1-NPL4 complex in protein quality control, discuss how its dysfunction leads to disease, and explore ongoing strategies to target the complex.