A redox switch on CDC48 regulates peroxisomal function via controlling peroxisome-associated protein degradation

Peroxisomes are single-membrane-bound organelles essential for diverse metabolic reactions and cellular redox homeostasis, yet the contribution of ubiquitin-proteasome system to peroxisomal biology remains unclear. Here, we demonstrate that the AAA-ATPase complex comprising Cell Division Cycle48 (CDC48), Nuclear Protein Localization4 (NPL4) and Ubiquitin Fusion Degradation1 (UFD1) is indispensable for peroxisomal biogenesis and physiological function in Arabidopsis. We identify the peroxisomal membrane peroxin PEX22 as a direct substrate of the CDC48 complex and show that this complex promotes ubiquitin-dependent PEX22 turnover. Genetic analyses place CDC48 complex upstream of PEX22 in controlling peroxisomal biogenesis and activity. Moreover, H₂O₂‑triggered Cys271 oxidation represses CDC48 ATPase activity, stabilizing PEX22 via slowed degradation; nucleoredoxin NRX1 reduces oxidized CDC48 to recover its function. Consistently, transgenic plants harboring the redox-insensitive CDC48-C271S variant display accelerated PEX22 turnover and enhanced susceptibility to oxidative stress. Collectively, our findings establish the CDC48 complex as a putative H₂O₂ sensor that governs ubiquitin-mediated peroxisome-associated protein degradation (PexAD), enabling fine-tuning of peroxisomal performance in plant development and upon environmental stress. Peroxisomes are essential for diverse biological functions. Here the authors show that H₂O₂‑triggered oxidation of the CDC48 AAA-ATPase complex in Arabidopsis regulates PEX22 abundance and fine-tunes peroxisomal activity.