Inhibition of E3 ligase Pellino-1 attenuates chronic obstructive
pulmonary disease and lung cellular senescence by promoting p21
degradation
Abstract
Background and Purpose Chronic obstructive pulmonary diseases (COPD) are
age-related, airflow-obstruction diseases mostly caused by cigarette
smoke. However, the relationship between COPD and lung cellular
senescence is still not fully understood. Here, we investigated how E3
ligase Pellino-1 mediated COPD and lung cellular senescence.
Experimental Approach We used western blot, qPCR and co-IP assays to
analyze the correlation of Pellino-1 and P21 in cells with or without
silencing Pellino-1. Then we used flow cytometry, immunofluorescence
staining and β- galactosidase assay to analyze the influences of
silencing Pellino-1. Furthermore, we constructed COPD and aging models
in vivo. Adenovirus of knock-down and overexpression Pellino-1 was used
to infected mice. Immunohistochemistry and HE staining were used to
analyze the lung pathology. Key Results Here, we first found that the E3
ubiquitin ligase Pellino-1 could bind to senescence marker p21 and
modify p21 by K63-site ubiquitination and verified with silencing
Pellino-1. Furthermore, we found that p21-mediated lung cellular
senescence could be inhibited by silencing Pellino-1. Moreover, by
constructing an adenovirus mouse model, we found that silencing
Pellino-1 could inhibit COPD and inflammation via reduction of SASPs
regulated by p21. Resistomycin, a potential Pellino-1 inhibitor,
interrupts the interaction between Pellino-1 and p21, which accelerates
the ubiquitin-dependent degradation of p21 and consequently inhibits
lung cellular senescence and COPD progression. Conclusion and
Implications Our study elucidated that inhibition of E3 ligase Pellino-1
exhibits therapeutic potential for treatment to attenuate the
progression of lung cellular senescence and COPD.