Plasmodium berghei liver stage parasites exploit host GABARAP proteins for TFEB activation

Area of Science:

• Cell Biology
• Parasitology
• Infectious Diseases

Background:

• Malaria parasites (Plasmodium) infect liver cells, residing in a parasitophorous vacuole (PV).
• Host cell autophagy pathways are crucial for Plasmodium liver-stage development.
• Transcription factor EB (TFEB) regulates autophagy and lysosomal genes.

Purpose of the Study:

• To investigate TFEB activation in Plasmodium berghei-infected liver cells.
• To elucidate the role of autophagy-related proteins in host cell signaling at the PV membrane (PVM).

Main Methods:

• Studied Plasmodium berghei-infected hepatocytes.
• Investigated the recruitment of FLCN-FNIP complex to the PVM.
• Analyzed the role of ATG8 proteins, including GABARAP subfamily members, in TFEB activation.

Main Results:

• Identified GABARAP proteins (ATG8 family) mediating FLCN-FNIP complex recruitment to the PVM.
• Demonstrated that GABARAP-dependent sequestration of FLCN-FNIP robustly activates TFEB.
• Showcased the importance of conjugation of ATG8 proteins to single membranes (CASM) and GABARAP proteins in this process.

Conclusions:

• Uncovered a novel mechanism of host cell signaling at the PVM during Plasmodium infection.
• Highlighted the critical role of GABARAP proteins in modulating TFEB activity via the FLCN-FNIP complex.
• Provided mechanistic insights into the Plasmodium-host cell interplay during the liver stage.