Derlin-1 and TER94/VCP/p97 are required for intestinal homeostasis.

Area of Science:

• Cell Biology
• Developmental Biology
• Genetics

Background:

• Adult stem cells are crucial for tissue homeostasis and repair.
• The precise mechanisms linking protein homeostasis to stem cell function remain incompletely understood.
• Endoplasmic reticulum-associated degradation (ERAD) is a key cellular protein quality control pathway.

Purpose of the Study:

• To investigate the role of ERAD components in regulating intestinal stem cell proliferation and tissue homeostasis in adult Drosophila.
• To elucidate the molecular mechanisms by which ERAD influences stem cell behavior.

Main Methods:

• Utilized Drosophila melanogaster as a model organism.
• Genetically manipulated the expression of ERAD components Derlin-1 and TER94/VCP/p97 in intestinal stem cells.
• Assessed stem cell proliferation, midgut homeostasis, reactive oxygen species (ROS) levels, and JNK signaling pathways.

Main Results:

• Depletion of Derlin-1 or TER94 led to increased intestinal stem cell proliferation and disrupted midgut homeostasis.
• Derlin-1's C-terminus is essential for its function in maintaining homeostasis.
• Elevated ROS levels and activated JNK signaling were identified as key mediators of increased proliferation in ERAD-deficient progenitors.
• Inhibition of ROS production or JNK signaling rescued the hyperproliferation phenotype.

Conclusions:

• The ERAD pathway plays a critical role in restraining stem cell proliferation and maintaining intestinal homeostasis.
• ERAD maintains tissue homeostasis by controlling ROS levels and JNK signaling.
• These findings provide insights into the link between protein quality control, stem cell biology, and potential implications in tumor development.