CALCOCO2/NDP52 initiates selective autophagy through recruitment of ULK and TBK1 kinase complexes

Area of Science:

• Cell Biology
• Molecular Biology
• Immunology

Background:

• Selective macroautophagy targets specific cargo for degradation via the autophagy machinery.
• The origin of phagophore membranes during selective autophagy (recruitment vs. de novo generation) at the cargo site remains unclear.

Purpose of the Study:

• To investigate the mechanism of phagophore membrane formation at damaged Salmonella-containing vacuoles during selective autophagy.
• To elucidate the role of cargo receptors and autophagy-initiating complexes in this process.

Main Methods:

• Utilized damaged Salmonella-containing vacuoles as a model system.
• Investigated the recruitment and function of autophagy-related proteins, including LGALS8 (galectin-8), CALCOCO2 (NDP52), ULK complex, TBK1 complex, and WIPI2.

Main Results:

• Damaged Salmonella-containing vacuoles, identified by LGALS8, engage the CALCOCO2 receptor.
• CALCOCO2 recruits the ULK and TBK1 kinase complexes, leading to the formation of WIPI2-positive phagophore membranes at the cargo.
• CALCOCO2 acts as a scaffold, forming a trimer with RB1CC1/FIP200 and TBKBP1/SINTBAD-AZI2/NAP1 to integrate the ULK and TBK1 complexes.

Conclusions:

• The study reveals that phagophore membranes are generated at the cargo site through the recruitment of the autophagy machinery.
• Demonstrates how the detection of cargo-associated signals integrates with the induction of autophagy and phagophore assembly in eukaryotes.