Researchers from China have identified ubiquitin-specific protease 13 (USP13) as a regulator of autophagy and age-related lung fibrosis in a mouse model. The results of their study were recently published in the American Journal of Respiratory Cell and Molecular Biology and contribute to current knowledge on the pathogenesis of idiopathic pulmonary fibrosis (IPF).

“We hypothesize that age-dependent USP13-mediated dysregulation of autophagic responses to stress enhances susceptibility to lung fibrosis by impairing proteostasis in epithelial cells; in the context of injury, this leads to activation of a fibrotic cascade,” Liu et al wrote.

General and alveolar type 2 cell-specific USP13 expression were decreased in lung tissues of patients with IPF compared to those in control subjects. The decrease in USP13 expression was shown to be age-dependent in mice with bleomycin (BLM)-induced pulmonary fibrosis.


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Liu et al found that aged Usp13-deficient mice were more prone to BLM-induced pulmonary fibrosis than mice with normal USP13 expression. Moreover, they exhibited a more prominent senescence-associated secretory phenotype in the lung tissue and bronchoalveolar lavage fluid.

Read more about the etiology of IPF

The results also implicated USP13 in the regulation of autophagy. USP13 downregulation decreased autophagic activity in the lungs of Usp13-deficient mice as indicated by the decrease in LC3B II and accumulation of p62 in lung tissue. The impairment of autophagic activity in Usp13-deficient mice was still observed in situations of BLM-induced stress.

Molecular studies suggested that USP13 interacted with the autophagic regulator Beclin-1, modulating its levels through deubiquitination. On the other hand, the role of USP13 in autophagy is dependent on Beclin-1. Beclin-1 knockdown impaired autophagy and increased the susceptibility of aged mice to BLM-induced pulmonary fibrosis.

Aged male mice with BLM-induced pulmonary fibrosis remain the most relevant preclinical model to study IPF.

Reference

Liu Y, Li Z, Xiao H, et al. USP13 deficiency impairs autophagy and facilitates age-related lung fibrosis. Am J Respir Cell Mol Biol. Published online September 23, 2022. doi:10.1165/rcmb.2022-0002OC