GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE344nnn/GSE344459/primary200OKTranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE344459GEOGSEfalseOptineurin-deficiency Collapses the Host Endolysosomal Network and Impairs Xenophagy to Accelerate Mycobacterium tuberculosis GrowthSelective autophagy is a host defense mechanism against Mycobacterium tuberculosis (Mtb) that restricts bacterial growth by targeting ubiquitin-coated bacilli for lysosomal degradation via autophagy receptors. Optineurin is a selective autophagy receptor that targets pathogens and modulates immune signaling, yet its precise structural mechanism during Mtb infection remains poorly defined. Here, we show that while Optineurin-deficiency spares the global host transcriptomic response to infection, it collapses the host endolysosomal network, decreasing LAMP1⁺ and LysoTracker⁺ reserves by half. Multi-dose bafilomycin A1 flux assays demonstrated that this structural depletion selectively blocks the dynamic, directional trafficking and functional delivery of autophagosomes to the pathogen, significantly reducing Mtb-DQ-BSA colocalization. Genetic complementation restored bacterial restriction in a manner dependent on three phosphosites (Ser187, Ser530, and the uncharacterized Ser556). In the context of reduced autophagic containment and increased Mtb replication, Optineurin-deficiency accelerated necrotic-like host cell death. In vivo, Optineurin-deficiency enhanced bacterial replication and impaired the Type I interferon response during acute Mtb infection but did not affect long-term survival. Together, these findings identify Optineurin as a critical regulator of autophagic flux, host cell death, and Type I interferon responses that limit early Mtb pathogenesis.2026/08/25GSE344459GSM9979302GSM9979303GSM9979300GSM9979301GSM9979306GSM9979304GSM9979305GSM9979295GSM9979298GSM9979299GSM9979296GSM997929734290344459Mus musculus