A Non-stop identity complex (NIC) supervises enterocyte identity and protects from premature aging

Area of Science:

• Cellular biology
• Aging research
• Drosophila melanogaster model systems

Background:

• Cellular identity loss is a key aging hallmark.
• Aged Drosophila midgut enterocytes (ECs) lose identity, impacting tissue function.
• Identifying regulators of cell identity is crucial for understanding aging.

Purpose of the Study:

• To identify genes regulating cell identity in Drosophila ECs.
• To investigate the role of the deubiquitinase Non-stop in maintaining EC identity.
• To elucidate the molecular mechanisms by which Non-stop influences aging phenotypes.

Main Methods:

• RNA interference (RNAi) screen targeting ubiquitin-related genes in ECs.
• Lineage tracing to track cell identity changes.
• Proteomic analysis to identify interacting protein complexes.
• Chromatin accessibility assays.

Main Results:

• An RNAi screen identified 17 candidate genes, including Non-stop.
• Loss of Non-stop in young ECs mimicked aged EC phenotypes.
• Non-stop forms a complex (NIC) with E(y)2, Sgf11, Cp190, (Mod)mdg4, and Nup98.
• Non-stop maintains chromatin accessibility and EC-specific gene expression.
• Aging reduces Non-stop and NIC levels, disrupting nuclear organization.

Conclusions:

• Non-stop and the Non-stop Identity Complex (NIC) are critical for maintaining EC identity.
• Non-stop safeguards NIC subunit stability and nuclear organization.
• Restoring Non-stop levels in aged cells reverses aging phenotypes and preserves tissue homeostasis.