Genetic dissection of rapid proteolysis identifies TXNDC15 as a key factor of ERAD and lipid homeostasis

Biological systems face a constantly changing environment and must swiftly respond to stimuli, yet how cells sense and adapt to environmental and physiological cues is incompletely understood. Short-lived proteins can be rapidly induced upon perturbation, enabling swift activation of adaptive cellular responses. Leveraging genome-wide data on protein-transcript correlation, we systematically searched for rapid proteolysis substrates whose abundance reflects the activity of the underlying proteolytic machinery. Here, focusing on the candidate substrate ABHD2, we employed CRISPR-based functional screens to dissect its degradation and identified TXNDC15 as an essential factor in MARCHF6-mediated ER-associated protein degradation (ERAD). Unexpectedly, TXNDC15 supports substrate exit and degradation from the ER via a catalysis-independent mechanism. Loss of TXNDC15 remodels the ER proteome and lipid homeostasis. Together, our work defines a missing component of ERAD and provides a generalizable strategy to decode post-translational regulatory circuits.