Transcription Factor EB SUMOylation in Airway Epithelial Cells Impairs Lysosomal Biogenesis to Promote Asthma Development.

Lysosomal dysfunction is the primary cause of various immune disorders. Transcription factor EB (TFEB) SUMOylation is critically involved in lysosomal biogenesis. Whether TFEB SUMOylation-associated lysosomal dysfunction contributes to asthma pathogenesis remains to be determined. Here, we observed that ovalbumin stimulation impaired lysosomal function through TFEB SUMOylation, which leads to increased NLRP3 and inflammatory factors. Mechanistically, mutation of the TFEB SUMOylation site did not abolish the ability of its nuclear translocation but increased TFEB stability and binding capability with target genes' promoters, thereby promoting lysosomal biogenesis and bioactivity through liquid-liquid phase separation and thus inhibiting the production of inflammatory factors and alleviating allergic airway inflammation. Our observations demonstrate that TFEB SUMOylation interferes with lysosomal biogenesis, contributing to asthma pathogenesis and lending mechanistic insight into asthmatic disease and improving our understanding of the transcriptional regulation of host immune responses.