Optineurin Deficiency Collapses the Host Endolysosomal Network and Impairs Xenophagy to Accelerate Mycobacterium tuberculosis Growth

Optineurin deficiency undermines the host endolysosomal network and hampers xenophagy, enabling rapid proliferation of Mycobacterium tuberculosis (Mtb), according to a recent study. Selective autophagy, a host defense mechanism against Mtb, targets ubiquitin-coated bacilli for lysosomal degradation via autophagy receptors. Optineurin, a key player in this process, remains underexplored in terms of its structural mechanism during Mtb infection.

The research reveals that while Optineurin deficiency does not alter the overall host transcriptomic response to infection, it disrupts the host endolysosomal network, halving the reserves of LAMP1+ and LysoTracker+. Multi-dose bafilomycin A1 flux assays confirm that this depletion specifically impedes the dynamic, directional trafficking and functional delivery of autophagosomes to the pathogen, drastically reducing Mtb-DQ-BSA colocalization.

Genetic complementation restores bacterial restriction through modifications at three phosphosites (Ser187, Ser530, and the uncharacterized Ser556). In the face of diminished autophagic containment and heightened Mtb replication, Optineurin deficiency triggers necrotic-like host cell death. In vivo observations show that Optineurin deficiency augments bacterial replication and impairs the Type I interferon response during acute Mtb infection, albeit without influencing long-term survival.

These findings underscore Optineurin's crucial role in regulating autophagic flux, host cell death, and Type I interferon responses, which are pivotal in controlling early Mtb pathogenesis.