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Updated: Sep 21, 2025
High Content Screening in Neurodegenerative Diseases
Published on: January 6, 2012
DJ-1 binds to Rubicon to Impair LC-3 Associated Phagocytosis
Sahil Gupta1,2, Hajera Amatullah1,3,4, James N Tsoporis1
1The Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, 209 Victoria Street, Toronto, ON, M5B1T8, Canada.
Abstract:
The ability to effectively clear infection is fundamental to host survival. Sepsis, defined as dysregulated host response to infection, is a heterogenous clinical syndrome that does not uniformly clear intact bacterial or sterile infection (i.e., lipopolysaccharide). These findings were further associated with increased survival in DJ-1 deficient animals exposed to intact bacteria relative to DJ-1 deficient challenged with lipopolysaccharide. We analyzed bacterial and lipopolysaccharide clearance in bone marrow macrophages (BMM) cultured ex vivo from wild-type and DJ-1 deficient mice. Importantly, we demonstrated that DJ-1 deficiency in BMM promotes Rubicon-dependent increase in L3C-associated phagocytosis, non-canonical autophagy pathway used for xenophagy, during bacterial but not lipopolysaccharide infection. In contrast to DJ-1 deficient BMM challenged with lipopolysaccharide, DJ-1 deficient BMM exposed to intact bacteria showed enhanced Rubicon complexing with Beclin-1 and UVRAG and consistently facilitated the assembly of complete autophagolysosomes that were decorated with LC3 molecules. Our data shows DJ-1 impairs or/and delays bacterial clearance and late autophagolysosome formation by binding to Rubicon resulting in Rubicon degradation, decreased L3C-associated phagocytosis, and decreased bacterial clearance in vitro and in vivo - implicating Rubicon and DJ-1 as critical regulators of bacterial clearance in experimental sepsis.
Insights
DJ-1 deficiency enhances bacterial clearance by promoting Rubicon-dependent autophagy. This pathway aids in clearing intact bacteria but not sterile lipopolysaccharide, highlighting DJ-1 and Rubicon
Area of Science:
- Immunology
- Cell Biology
- Microbiology
Background:
- Effective infection clearance is vital for host survival.
- Sepsis is a complex syndrome characterized by a dysregulated host response to infection.
- Current understanding of infection clearance mechanisms, particularly in sepsis, remains incomplete.
Purpose of the Study:
- To investigate the role of DJ-1 in bacterial and lipopolysaccharide clearance.
- To elucidate the molecular mechanisms underlying DJ-1's function in infection clearance.
- To determine the interplay between DJ-1, Rubicon, and autophagy in sepsis.
Main Methods:
- Ex vivo analysis of bone marrow macrophages (BMM) from wild-type and DJ-1 deficient mice.
- Assessment of bacterial and lipopolysaccharide clearance.
- Investigation of autophagy pathways, including Rubicon-dependent phagocytosis and autophagolysosome formation.
Main Results:
- DJ-1 deficiency enhanced bacterial clearance and promoted Rubicon-dependent LC3-associated phagocytosis (LAP) in BMM during bacterial infection.
- DJ-1 deficiency did not enhance lipopolysaccharide clearance, indicating specificity in pathogen response.
- DJ-1 deficiency led to increased Rubicon complexation with Beclin-1 and UVRAG, facilitating autophagolysosome assembly during bacterial infection.
Conclusions:
- DJ-1 impairs bacterial clearance and autophagolysosome formation by binding to Rubicon, leading to Rubicon degradation.
- DJ-1 deficiency enhances Rubicon-dependent phagocytosis and bacterial clearance in vitro and in vivo.
- Rubicon and DJ-1 are critical regulators of bacterial clearance in experimental sepsis.
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