Burkholderia pseudomallei BipD modulates host mitophagy to evade killing

Area of Science:

• Cell Biology
• Microbiology
• Immunology

Background:

• Mitophagy is a crucial cellular mechanism for maintaining mitochondrial health and function by removing damaged mitochondria.
• Intracellular bacterial pathogens often evolve strategies to manipulate host cell processes for their survival and replication.

Purpose of the Study:

• To investigate the mechanism by which Burkholderia pseudomallei utilizes host mitophagy for intracellular survival.
• To identify the bacterial factors and host proteins involved in this manipulation.

Main Methods:

• Identified the bacterial protein BipD as a key effector.
• Investigated interactions between BipD and host proteins KLHL9, KLHL13, and CUL3 using biochemical assays.
• Utilized host ubiquitome profiling to identify mitochondrial substrates.
• Performed ubiquitination assays and assessed mitophagy induction in mouse macrophages.

Main Results:

• BipD interacts with KLHL9/KLHL13/CUL3 E3 ligase complex, mediating BipD-dependent mitochondrial ubiquitination.
• The inner mitochondrial membrane protein IMMT was identified as a substrate of the KLHL9/KLHL13/CUL3 complex.
• K63-linked ubiquitination of IMMT at K211 by this complex is essential for initiating mitophagy.
• This process reduces mitochondrial reactive oxygen species (ROS) production, facilitating bacterial survival.

Conclusions:

• Burkholderia pseudomallei employs a novel mechanism involving the type III secretion system protein BipD to hijack host mitophagy.
• The bacterial manipulation targets the IMMT protein for ubiquitination, triggering mitophagy and suppressing ROS.
• This study reveals a unique bacterial strategy to exploit host mitochondrial quality control for intracellular survival.