Brucella activates the host RIDD pathway to subvert BLOS1-directed immune defense

Abstract

The phagocytosis and destruction of pathogens in lysosomes constitute central elements of innate immune defense. Here, we show that Brucella, the causative agent of brucellosis, the most prevalent bacterial zoonosis globally, subverts this immune defense pathway by activating regulated IRE1α-dependent decay (RIDD) of Bloc1s1 mRNA encoding BLOS1, a protein that promotes endosome–lysosome fusion. RIDD-deficient cells and mice harboring a RIDD-incompetent variant of IRE1α were resistant to infection. Inactivation of the Bloc1s1 gene impaired the ability to assemble BLOC-1-related complex (BORC), resulting in differential recruitment of BORC-related lysosome trafficking components, perinuclear trafficking of Brucella-containing vacuoles (BCVs), and enhanced susceptibility to infection. The RIDD-resistant Bloc1s1 variant maintains the integrity of BORC and a higher-level association of BORC-related components that promote centrifugal lysosome trafficking, resulting in enhanced BCV peripheral trafficking and lysosomal destruction, and resistance to infection. These findings demonstrate that host RIDD activity on BLOS1 regulates Brucella intracellular parasitism by disrupting BORC-directed lysosomal trafficking. Notably, coronavirus murine hepatitis virus also subverted the RIDD–BLOS1 axis to promote intracellular replication. Our work establishes BLOS1 as a novel immune defense factor whose activity is hijacked by diverse pathogens.

The IRE1α-XBP1 Signaling Axis Promotes Glycolytic Reprogramming in Response to Inflammatory Stimuli

“…In addition to splicing the XBP1 transcript, activated IRE1α also degrades specific RNA species in a process called regulated IRE1α-dependent decay, or RIDD. Intriguingly, RIDD, which contributes to the intracellular survival of Brucella ( 28 ), influences the metabolism of cancer cells ( 52 ) and thus may also be affecting CAM metabolism.…”

“…Many intracellular pathogens induce ER stress in their host cells ( 20 , 21 ), including Brucella spp., which use their type IV secretion systems (T4SS) to interact extensively with the ER ( 22 ), ultimately leading to UPR activation ( 23 – 27 ). IRE1α has been shown to be phosphorylated upon Brucella infection ( 23 , 28 ) and to form puncta throughout infected cells ( 23 ). Though it is well established that IRE1α plays an important role in the development and effector functions of immune cells, the links between IRE1α activation and innate immunity remain poorly understood.…”

The IRE1α-XBP1 signaling axis promotes glycolytic reprogramming in response to inflammatory stimuli

“…In addition to splicing the XBP1 transcript, activated IRE1α also degrades specific RNA species in a process called regulated IRE1α-dependent decay, or RIDD. Intriguingly, RIDD, which contributes to the intracellular survival of Brucella (28), influences the metabolism of cancer cells (52) and thus may also be affecting the metabolism of CAM.…”

“…Many intracellular pathogens induce ER stress in their host cells (20,21), including Brucella spp., which use their type IV secretion systems (T4SS) to interact extensively with the ER (22), ultimately leading to UPR activation (23)(24)(25)(26)(27). IRE1α has been shown to be phosphorylated upon Brucella infection (23,28) and to form puncta throughout infected cells (23). Though it is well established that IRE1α plays an important role in the development and effector functions of immune cells, the links between IRE1α activation and innate immunity remain poorly understood.…”

Validation of GCN5L1/BLOC1S1/BLOS1 Antibodies Using Knockout Cells and Tissue

“…Subsequent studies have shown that GCN5L1 is involved in endosome-to-vacuole transport in Arabidopsis (Cui et al, 2010), the development of lysosome-related organelles in Zebrafish (Chen et al, 2018), and lysosomal trafficking in mouse liver (Wu et al, 2018). More recently, these endo-lysosomal processes have implicated GCN5L1 in the control of stress-related lysosomal positioning (Bae et al, 2019), LDL receptor recycling (Zhang et al, 2020), bacterial innate immune pathways (Wells et al, 2022), and hepatic lysosomal lipolysis (Wu et al, 2023).…”