E3 Ubiquitin Ligase March1 Facilitates OX40L Expression in Allergen-Stimulated Dendritic Cells Through Mediating the Ubiquitination of HDAC11

Abstract

Background: It was demonstrated that membrane-associated RING-CH 1 (March 1) might play an important role in the pathogenesis of asthma. Methods: The levels of mRNA and protein were measured by qRT-PCR and Western blot, respectively. Immunofluorescence assay was used to determine whether March1 co-locates with HDAC11. Co-immunoprecipitation was performed to examine the combination of proteins. Moreover, luciferase assay was used to measure the promoter activity of genes. Results: The mRNA and protein levels of both March1 and OX40 ligand (OX40L) were increased in the dendritic cells (DCs) from asthmatic children and asthmatic animals. Histone deacetylase 11 (HDAC11) protein was decreased in the DCs from asthmatic children and asthmatic model. Increasing of March1 or decreasing of March1 only affect the expression of HDAC11 in protein level. Besides, increasing of HDAC11 could inhibit OX40L expression, and decreasing of HDAC11 promoted OX40L expression in house dust mites (HDMs)-treated DCs. Increasing of HDAC11 notably reversed the promotion of March1 to OX40L expression. Our data further proved that March1 reduced the protein level of HDAC11 through inducing ubiquitination and degradation. HDAC11 combined with krüppel-like factor 4 (KLF4) to decrease the activity of OX40L gene promoter, thus to downregulate the level of OX40L. Conclusion: Overall, our data showed that HDAC11 promoted KLF4-dependent OX40L decreasing. However, March1 promoted OX40L expression through enhancing the ubiquitination and degradation of HDAC11 and subsequent blocking the inhibition of HDAC11 to OX40L.

Targeting psychological stress-steroid-MARCH1 signaling pathway promotes the efficacy of specific allergen immunotherapy

“…Rs reduced the IL-10 expression in DCs. MARCH1 is an E3 ligase, which can induce ubiquitination in targeted proteins to induce the protein degradation 17 . Thus, immunoprecipitation (IP) was performed with protein extracts of DC using an anti-MARCH1 Ab as a bait.…”

“…Based on the indication that Rs increases cortisol release, we found that cortisol was associated with the increased MARCH1 expression in DCs of the mice exposed to Rs. MARCH1 is an E3 ligase and can help target protein breakdown 17 . Recent studies have also shown that MARCH1 interferes with immune regulatory functions, particularly by favoring Th2 polarization 15 .…”

Decreased ubiquitin modifying enzyme A20 associated with hyper-responsiveness to ovalbumin challenge following intrauterine growth restriction

“…Recently, more and more studies have also identified the ubiquitination as a central process in the pathogenesis and development of asthma [ 23 , 25 ]. Ubiquitination also indirectly participated in the pathogenesis of asthma through regulating functions of macrophage and dendritic cells [ 26 , 27 ].…”