Abstract
Tuberculosis remains a leading health problem worldwide and still accounts for about 1.3 million deaths annually. Expression of the mouse Sp110 nuclear body protein (Sp110) upregulates the apoptotic pathway, which plays an essential role in enhancing host immunity to Mycobacterium tuberculosis (Mtb). However, the mechanism of this upregulation is unclear. Here, we have identified 253 proteins in mouse macrophages that interact with Sp110, of which 251 proteins were previously uncharacterized. The results showed that Sp110 interacts with heat shock protein 5 (Hspa5) to activate endoplasmic reticulum (ER) stress-induced apoptosis, and that this is essential for Sp110 enhanced macrophage resistance to Mtb. Inhibition of the ER stress pathway abolishing the Sp110-enhanced macrophage apoptosis and resulted in increased intracellular survival of Mtb in macrophages overexpressing Sp110 Further studies revealed that Sp110 also interacts with the RNA binding protein, Ncl to promote its degradation. Consequently, the expression of Bcl2, usually stabilized by Ncl, was downregulated in Sp110 overexpressing macrophages. Moreover, overexpression of Sp110 promotes degradation of ribosomal protein Rps3a, resulting in upregulation of the activity of the pro-apoptotic poly (ADP-ribose) polymerase (PARP). In addition, macrophages from transgenic cattle with increased Sp110 expression confirmed that activation of the ER stress response is the main pathway through which Sp110-enhanced macrophages impart resistance to Mtb. This work has revealed the mechanism of Sp110 enhanced macrophage apoptosis in response to Mtb infection, and provides new insights into the study of host-pathogen interactions.
Highlights
Tuberculosis is caused by the intracellular pathogen Mycobacterium tuberculosis (Mtb)and remains a major human health problem worldwide, infecting a large number of people, making eradication difficult
The results showed that Sp110 interacts with heat shock protein 5 (Hspa5) to activate endoplasmic reticulum (ER) stress-induced apoptosis, and that this is essential for Sp110 enhanced macrophage resistance to Mtb
We found that treatment with 4-phenyl butyric acid (4-PBA) enhanced survival of Bacillus Calmette-Guerin (BCG) in macrophages derived from Sp110 transgenic cattle (Figure 7D). These results suggested that Sp110 induces ER stress in bovine macrophages, and this is crucial for Sp110-enhanced resistance of bovine macrophages to BCG infection
Summary
Tuberculosis is caused by the intracellular pathogen Mycobacterium tuberculosis (Mtb)and remains a major human health problem worldwide, infecting a large number of people, making eradication difficult. Kramnik et al identified a genetic locus on mouse chromosome 1 that designated susceptibility to tuberculosis 1 (sst1), and primarily controls the progression of tuberculosis infection [4]. Subsequent studies identified the intracellular pathogen resistance 1 gene ( known as Sp110) within the sst locus which enhances innate immunity to Mtb. Transgenic mouse macrophages overexpressing Sp110 were able to reduce multiplication of Mtb efficiently and activate the apoptotic pathway upon infection with virulent Mtb [5]. We reported that overexpression of mouse Sp110 enhances the host’s resistance to virulent Mycobacterium bovis (M. bovis) both in vivo and in vitro [6, 7]. The molecular mechanism of Sp110 enhances macrophage resistance to Mtb infection remains unknown
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