Derlin-1 regulates mutant VCP-linked pathogenesis and endoplasmic reticulum stress-induced apoptosis

Area of Science:

• Cell Biology
• Neuroscience
• Molecular Biology

Background:

• Mutations in Valosin-containing protein (VCP) are associated with Inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD).
• VCP is an AAA ATPase crucial for ER-associated degradation, a key cellular process.

Purpose of the Study:

• To investigate the role of the ER protein Derlin-1 in a Drosophila model of IBMPFD.
• To elucidate the interaction between Derlin-1 and the VCP homolog TER94 in the context of neurodegeneration and ER stress.

Main Methods:

• Utilized a Drosophila IBMPFD model to study VCP (TER94) mutants.
• Investigated the direct binding and functional interaction between Derlin-1 and TER94.
• Assessed the impact of Derlin-1 and TER94 overexpression on neurodegeneration and ATPase activity.
• Examined Derlin-1's role in ER stress response and apoptosis.

Main Results:

• Derlin-1 directly binds to TER94, and this interaction is vital for suppressing TER94-induced neurodegeneration.
• Overexpression of Derlin-1 reduces the elevated ATPase activity of pathogenic TER94 mutants, suggesting IBMPFD is linked to ATPase hyper-activation.
• Derlin-1 expression increases with ER stress to recruit TER94, but is also required for apoptosis under severe ER stress.
• Derlin-1 overexpression mimics this pro-apoptotic response via a novel C-terminal motif, an effect negated by TER94 overexpression.

Conclusions:

• Derlin-1 acts as a modifier of pathogenic VCP/TER94 mutants in IBMPFD.
• The VCP-Derlin-1 interaction is critical for cellular response to ER stress and maintaining proteostasis.
• Imbalance in the Derlin-1 and VCP pathway contributes to cell removal during prolonged ER stress, offering insights into IBMPFD pathogenesis.