Mycobacterial SapM hampers host autophagy initiation for intracellular bacillary survival via dephosphorylating Raptor.

Secreted acid phosphatase (SapM) is an immunomodulator of Mycobacterium tuberculosis (Mtb) and consequently plays a crucial role in disease onset and development upon infection. Importantly, the virulence of SapM has rendered SapM an attractive target for drug development. However, the mechanism underlying the role of SapM in facilitating bacillary survival remains to be fully elucidated. In this context, the present study demonstrated that SapM hampered cellular autophagy to facilitate bacillary survival in mycobacterial-infected macrophages. Mechanically, SapM interacted with Raptor and was localized to the subcellular lysosomal organelle, causing the dephosphorylation of Raptor at the Ser792 position, resulting in mTORC1 hyperactivity and the subsequent autophagy inhibition. Consistent with this, SapM blocked the autophagy initiation and mitigated lung pathology in vivo. These findings highlighted the role of Raptor as a significant substrate of SapM for inhibiting autophagy, which is a novel clue for developing a treatment against tuberculosis.

Mycobacterial Rv1804c binds to the PEST domain of IκBα and activates macrophage-mediated proinflammatory responses.

Recognition of the components of Mycobacterium tuberculosis (Mtb) by macrophages is vital for initiating a cascade of host immune responses. However, the recognition of Mtb-secretory proteins by the receptor-independent pathways of the host remains unclear. Rv1804c is a highly conserved secretory protein in Mtb. However, its exact function and underlying mechanism in Mtb infection remain poorly understood. In the present study, we observed that Rv1804c activates macrophage-mediated proinflammatory responses in an IKKα-independent manner. Furthermore, we noted that Rv1804c inhibits mycobacterial survival. By elucidating the underlying mechanisms, we observed that Rv1804c activates IκBα by directly interacting with its PEST domain. Moreover, Rv1804c was enriched in attenuated but not in virulent mycobacteria and associated with the disease process of tuberculosis. Our findings provide an alternative pathway via which a mycobacterial secretory protein activates macrophage-mediated proinflammatory responses. Our study findings may shed light on the prevention and treatment of tuberculosis.

ALS-linked C9orf72 dipeptide repeats inhibit starvation-induced autophagy through modulating BCL2-BECN1 interaction.

Growing evidences indicate that dysfunction of autophagy contributes to the disease pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two neurodegenerative disorders. The GGGGCC·GGCCCC repeat RNA expansion in chromosome 9 open reading frame 72 (C9orf72) is the most genetic cause of both ALS and FTD. According to the previous studies, GGGGCC·GGCCCC repeat undergoes the unconventional repeat-associated non-ATG translation, which produces dipeptide repeat (DPR) proteins. Although there is a growing understanding that C9orf72 DPRs have a strong ability to harm neurons and induce C9orf72-linked ALS/FTD, whether these DPRs can affect autophagy remains unclear. In the present study, we find that poly-GR and poly-PR, two arginine-containing DPRs which display the most cytotoxic properties according to the previous studies, strongly inhibit starvation-induced autophagy. Moreover, our data indicate that arginine-rich DPRs enhance the interaction between BCL2 and BECN1/Beclin 1 by inhibiting BCL2 phosphorylation, therefore they can impair autophagic clearance of neurodegenerative disease-associated protein aggregates under starvation condition in cells. Importantly, our study not only highlights the role of C9orf72 DPR in autophagy dysfunction, but also provides novel insight that pharmacological intervention of autophagy using SW063058, a small molecule compound that can disrupt the interaction between BECN1 and BCL2, may reduce C9orf72 DPR-induced neurotoxicity.