SIVA-1 regulates apoptosis and synaptic function by modulating XIAP interaction with the death receptor antagonist...

Area of Science:

• Molecular and Cellular Neuroscience
• Apoptosis and Cell Death Signaling
• Synaptic Plasticity Mechanisms

Background:

• Fas apoptosis inhibitory molecule-like (FAIM-L) is a neuron-specific antagonist of apoptotic cell death.
• FAIM-L inhibits caspases by binding to X-linked inhibitor of apoptosis protein (XIAP), preventing XIAP degradation.
• This interaction also influences non-apoptotic caspase functions, including AMPA receptor (AMPAR) endocytosis during long-term depression (LTD).

Purpose of the Study:

• To identify novel FAIM-L interacting proteins using a two-hybrid screening.
• To elucidate the molecular mechanism by which FAIM-L regulates XIAP and caspase activity.
• To investigate the role of novel interacting proteins in synaptic function and neuronal plasticity.

Main Methods:

• Yeast two-hybrid screening to identify FAIM-L interacting partners.
• Co-immunoprecipitation and Western blotting to confirm protein interactions and ubiquitination.
• Caspase activity assays and assessment of AMPAR internalization in neuronal cultures.

Main Results:

• Identified SIVA-1 as a novel functional binding partner of FAIM-L.
• Demonstrated that SIVA-1 disrupts the FAIM-L-XIAP interaction, leading to XIAP ubiquitination and caspase-3 activation.
• Showed SIVA-1 modulates AMPAR internalization during chemical LTD via non-apoptotic caspase activation.

Conclusions:

• SIVA-1 acts as a novel regulator of FAIM-L function, promoting neuronal death by disrupting the FAIM-L-XIAP complex.
• SIVA-1 plays a critical role in synaptic plasticity, specifically AMPAR internalization, through caspase-dependent mechanisms.
• These findings reveal SIVA-1 as a key player in modulating both apoptotic and non-apoptotic signaling pathways in neurons.