Dual function of CALCOCO2/NDP52 during xenophagy

Area of Science:

• Cell Biology
• Immunology
• Microbiology

Background:

• Xenophagy is a cellular process where pathogens are degraded by the autophagy machinery.
• Autophagy receptors, like CALCOCO2 (also known as NDP52), play a role in targeting pathogens to autophagosomes.
• Previous research indicated CALCOCO2's involvement in targeting Salmonella Typhimurium.

Purpose of the Study:

• To investigate the complete role of the autophagy receptor CALCOCO2 in xenophagy.
• To elucidate the distinct mechanisms by which CALCOCO2 mediates pathogen targeting and autophagosome maturation.
• To identify the specific protein interactions involved in CALCOCO2's dual functions.

Main Methods:

• Studied the interactions of CALCOCO2 with autophagy-related proteins (LC3A, LC3B, LC3C, GABARAPL2) and MYO6 (MYOSIN VI).
• Investigated the binding domains and protein partners critical for CALCOCO2's targeting and maturation functions.
• Utilized cell-based assays to analyze the process of Salmonella Typhimurium xenophagy.

Main Results:

• CALCOCO2 targets Salmonella Typhimurium to phagophores by interacting with LC3C and ubiquitinated bacteria or galectins on damaged vacuoles.
• CALCOCO2 is essential for the maturation of Salmonella-containing autophagosomes, a function independent of its targeting role.
• Autophagosome maturation mediated by CALCOCO2 involves binding to LC3A, LC3B, or GABARAPL2 and MYO6, but not LC3C.

Conclusions:

• The autophagy receptor CALCOCO2 performs a dual role in xenophagy.
• CALCOCO2 first targets bacteria to nascent autophagosomes and subsequently promotes their maturation for degradation.
• These distinct functions are mediated by different protein interactions, highlighting the complexity of xenophagy regulation.