Rank normalization resolves distinct proteome degradation pathways in cultured cells

In cultured cells, researchers developed a rank-normalization method to directly compare how proteins are cleared by the ubiquitin proteasome system and the autophagy lysosomal pathway. The preprint reports combining pulse stable isotope labeling by amino acids in cell culture with selective pathway inhibitors. Direct comparisons typically suffer from mismatched dynamic ranges between different perturbations. By converting protein stabilization values into percentile ranks within each condition, the authors placed both systems onto a shared scale. Across two independent experiments, the authors quantified 5,518 proteins, obtaining high-confidence half-lives for 3,814 proteins across control, proteasome-inhibited, and lysosome-inhibited states. The analysis revealed relative clearance preferences across the proteome. Specifically, lysosomal inhibition led to the coordinated stabilization of proteasome core and regulatory subunits, offering proteome-wide quantitative support for proteaphagy.