Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1

Area of Science:

• Virology
• Cell Biology
• Immunology

Background:

• The influenza virus PB1-F2 protein is known to induce cell death, but its precise mechanism remains unclear.
• Understanding PB1-F2's role in apoptosis is crucial for comprehending viral pathogenesis and host responses.

Purpose of the Study:

• To elucidate the mechanism by which the influenza virus PB1-F2 protein induces apoptosis.
• To identify the mitochondrial targets of PB1-F2 and their role in cell death pathways.

Main Methods:

• Characterization of PB1-F2's effect on apoptosis in PB1-F2-expressing cells.
• Biochemical assays using purified mitochondria to assess PB1-F2's impact on mitochondrial integrity and cytochrome c release.
• Affinity purification coupled with mass spectrometry to identify PB1-F2's mitochondrial interactors.
• Assessment of permeability transition pore complex (PTPC) blockers on PB1-F2-induced mitochondrial permeabilization.

Main Results:

• PB1-F2 sensitizes cells to tumor necrosis factor alpha-induced apoptosis, evidenced by increased caspase 3 substrate cleavage.
• Recombinant PB1-F2 induces cytochrome c release and loss of mitochondrial membrane potential in isolated mitochondria.
• PB1-F2 uniquely interacts with adenine nucleotide translocator 3 (ANT3) and voltage-dependent anion channel 1 (VDAC1), key components of the PTPC.
• PTPC blockers inhibit PB1-F2-mediated mitochondrial permeabilization.

Conclusions:

• The influenza virus PB1-F2 protein induces apoptosis by directly acting on the mitochondrial permeability transition pore complex (PTPC).
• PB1-F2's interaction with ANT3 and VDAC1 facilitates mitochondrial permeabilization, contributing to cellular apoptosis.
• This mechanism suggests a potential role for PB1-F2 in down-regulating the host immune response during influenza infection.