Abstract
Toxoplasma gondii (T. gondii) is an obligate intracellular parasite that can infect almost all warm-blooded animals, causing serious public health problems. Lysine crotonylation (Kcr) is a newly discovered posttranslational modification (PTM), which is first identified on histones and has been proved relevant to procreation regulation, transcription activation, and cell signaling pathway. However, the biological functions of histone crotonylation have not yet been reported in macrophages infected with T. gondii. As a result, a total of 1,286 Kcr sites distributed in 414 proteins were identified and quantified, demonstrating the existence of crotonylation in porcine alveolar macrophages. According to our results, identified histones were overall downregulated. HDAC2, a histone decrotonylase, was found to be significantly increased, which might be the executor of histone Kcr after parasite infection. In addition, T. gondii infection inhibited the crotonylation of H2B on K12, contributing on the suppression of epigenetic regulation and NF-κB activation. Nevertheless, the reduction of histone crotonylation induced by parasite infection could promote macrophage proliferation via activating PI3K/Akt signaling pathway. The present findings point to a comprehensive understanding of the biological functions of histone crotonylation in porcine alveolar macrophages, thereby providing a certain research basis for the mechanism research on the immune response of host cells against T. gondii infection.
Highlights
As a member of the phylum Apicomplexa, Toxoplasma gondii (T. gondii) is an important food-borne and water-borne zoonotic pathogen [1]
It has never been clearly identified whether and how histone deacetylases (HDACs) regulate histone Kcr in macrophages infected with T. gondii
Western blot analysis using pan-Kcr antibody revealed that the levels of Kcr in porcine cells with silence of HDAC2 after T. gondii infection were similar to that of uninfected cells (Figure 6), and we further observed that the modification levels of H2BK12cr can be effectively recovered with silence of HDAC2, which indicated that HDAC2 was highly correlated with dynamic changes of Kcr induced by T. gondii stimulation (Figure 3D)
Summary
As a member of the phylum Apicomplexa, Toxoplasma gondii (T. gondii) is an important food-borne and water-borne zoonotic pathogen [1]. Previous research reported that the inhibition of class I HDAC1/2/3 leads to histone Kcr significant induction and affects gene expression and epigenome, thereby affecting cell function and regulating immune responses [28]. It has never been clearly identified whether and how HDACs regulate histone Kcr in macrophages infected with T. gondii. Our work provides comprehensive insights into the biological functions of histone crotonylation in porcine alveolar macrophages, which may pave the way for exploring the specific mechanisms of histone crotonylation in the immune response of host cells against T. gondii infection
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