Roles for a novel component in nucleophagy and chronological aging

Aging leads to a variety of changes at the subcellular level, including structural and functional alterations to the nuclear envelope and conversely, genetic defects affecting the nuclear envelope trigger premature aging. Autophagy becomes critical during aging to recycle unneeded or damaged cellular components and to lower the biosynthetic capacity to conform to reduced cellular demands. The nucleus is central in this regard as it represents the site of DNA replication, RNA transcription, ribosome assembly and lipid synthesis. We will focus on the molecular mechanism of nucleophagy: the autophagic degradation of regions of the nuclear envelope. Impaired nucleophagy, like impaired autophagy, leads to premature cell death during chronological aging. Using a systematic, unbiased, genetic screen we have found that deletion of a gene encoding a constituent of the nuclear envelope causes a tight block in the autophagic degradation of an outer nuclear membrane protein, Hmg1. We will test the role of this novel component on a variety of autophagic pathways to define the range and specificity of its function. Autophagic degradation of Hmg1 relies on the selective autophagy receptor, Atg39. Preliminary data suggests that the deletion mutant blocks delivery of Atg39 to the vacuole in response to nutrient limitation. The Atg39 delivery pathway has been defined at a morphological level and several biochemical and visual landmarks on this pathway have been reported. To identify the site of action of this novel component on the Atg39 pathway we will test the deletion mutant for its effect on the ultrastructure of the nuclear envelope at sites of Atg39 foci during nucleophagy and on key landmarks along the pathway. We will probe for interactions with Atg39 using a coprecipitation protocol and will test the effects of the deletion mutant on chronological aging using two independent assays. Project Number: 1R21AG100440-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: PETER NOVICK | Institution: UNIVERSITY OF CALIFORNIA, SAN DIEGO, LA JOLLA, CA | Award Amount: $439,750 | Activity Code: R21 | Study Section: Cell Structure and Function 1 Study Section[CSF1] View on NIH RePORTER: https://reporter.nih.gov/project-details/11352151