Pathological Substrate Hijacking of the Autophagy Hierarchy Drives Nuclear Lamina Dysfunction in Aging

Hypothesis

The autophagy machinery does not merely degrade cargo in a passive queue; it operates through a competitive hierarchy in which soluble selective autophagy receptors (SARs) – p62, NDP52, TAX1BP1, OPTN – vie for limited binding sites on the ULK complex scaffold FIP200 [Competitive SAR binding]. This competition creates a substrate prioritization code that determines which organelles or proteins are engulfed first. We propose that pathological substrates bearing aberrant post‑translational modifications (e.g., farnesylated progerin, hyper‑phosphorylated tau, or ubiquitin‑modified lipid droplets) acquire unusually high affinity for one or more SARs, thereby monopolizing FIP200 and starving the autophagy of physiological cargos such as damaged lamins, mitochondria, or protein aggregates. The resulting "hierarchy collapse" redirects autophagic capacity toward the pathological cargo, impairing nuclear lamina turnover and accelerating age‑related nuclear envelope dysfunction.

Mechanistic rationale

1. Affinity shift – SARs bind ubiquitin chains with differing preferences (p62 favors linear/K63 over K48) [Ubiquitin chain topology]. Pathological modifications can generate ubiquitin-like motifs or expose cryptic ubiquitin‑binding motifs that increase SAR affinity beyond physiological ligands.

2. Stoichiometric bottleneck – FIP200 is present at limiting concentrations; SAR–FIP200 interactions follow a simple competitive binding model. When a high‑affinity pathological substrate–SAR complex forms, it reduces the free FIP200 pool, decreasing the initiation rate for all other SARs (mass‑action competition).

3. Cargo‑induced nucleation – In selective autophagy independent of starvation, cargo recruits the ULK complex to itself [Cargo‑induced nucleation]. A pathological cargo that can act as a nucleation platform will thus sequester ULK/FIP200 locally, creating a positive feedback loop that further depletes soluble FIP200.

4. Nuclear lamina specificity – LC3 directly binds Lamin B1 via residues R10/R11, making lamins bona fide autophagy substrates [LC3‑Lamin B1]. When FIP200 is diverted, lamin‑LC3 encounters fail, leading to accumulation of farnesylated lamin A/progerin at the nuclear envelope, heightened nuclear shape defects, and impaired mechanotransduction.

Testable predictions

• Prediction 1: Overexpression of a high‑affinity SAR mutant (e.g., p62‑UBD with increased K63 binding) will reduce FIP200 availability for endogenous SARs, decreasing LC3‑Lamin B1 colocalization and increasing nuclear blebbing in cultured fibroblasts. This can be rescued by FIP200 overexpression.

• Prediction 2: Cells expressing farnesylated progerin will show increased p62‑progerin complexes and decreased free FIP200 measured by quantitative co‑immunoprecipitation or proximity ligation assay. Pharmacological disruption of the p62‑progerin interaction (using a competitive peptide) should restore FIP200 levels and improve lamin autophagy.

• Prediction 3: In vivo, Drosophila expressing a human high‑affinity SAR transgene in the fat body will exhibit shortened lifespan and nuclear envelope abnormalities, whereas concurrent overexpression of FIP200 will extend lifespan and ameliorate nuclear defects.

• Prediction 4: Quantitative mass‑spectrometry of ubiquitin chain types on pathological cargos will reveal enrichment of linear/K63 linkages correlating with SAR affinity shifts; mutating these linkages to K48 will abolish the hierarchy hijacking phenotype.

Falsifiability

If manipulation of SAR affinity or FIP200 levels fails to alter lysosomal delivery of lamins or nuclear morphology despite confirmed changes in substrate‑SAR binding, the hypothesis that hierarchy disruption drives lamina dysfunction would be falsified. Conversely, consistent rescue of lamin turnover by restoring FIP200 availability would support the model.