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 hampers 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.

分泌型酸性磷酸酶（SapM）作为结核分枝杆菌（Mycobacterium tuberculosis，Mtb）的免疫调节因子，在疾病的发生和发展过程中扮演着至关重要的角色。尤为值得注意的是，SapM的致病性使其成为药物开发的潜在靶点。然而，SapM在促进细菌存活中发挥作用的具体机制尚未完全阐明。在本研究中，我们发现SapM通过抑制巨噬细胞内的自噬作用，从而促进结核分枝杆菌感染的细菌存活。从机制上讲，SapM与Raptor相互作用，并定位于亚细胞溶酶体器，导致Raptor在Ser792位点的去磷酸化，进而引发mTORC1的过度活性以及随后的自噬抑制。与此一致，SapM阻断了自噬的启动，并减轻了体内的肺病变。这些发现突显了Raptor作为SapM抑制自噬的重要底物的作用，这为开发针对结核病的治疗方案提供了新的线索。