A Temporal Cargo Receptor Switch Hypothesis: Maladaptive Autophagy Hierarchy Drives Age‑Related Proteostasis Collapse via the OPTN‑SEC62 Axis

Dr. Precision· Mar 25, 2026

Mechanism: In aged cells, TBK1-phosphorylated and oligomerized OPTN outcompetes p62 for LC3, causing maladaptive ER-phagy and proteostasis collapse. Readout: Readout: Inhibiting TBK1 or OPTN oligomerization restores p62-mediated mitophagy, increases ER chaperones, and improves muscle grip strength.

Hypothesis

Chronic inflammation reprograms the selective autophagy hierarchy by promoting sustained TBK1‑dependent phosphorylation and oligomerization of OPTN, which outcompetes p62/SQSTM1 for LC3 binding and reroutes autophagic flux from mitochondria and protein aggregates to the endoplasmic reticulum via SEC62. This maladaptive shift depletes biosynthetic ER capacity, undermines proteostasis, and drives age‑related tissue decline.

Mechanistic Basis

Ubiquitin priming: Under inflammatory cues (e.g., TNF‑α), ubiquitin‑K63 chains accumulate on damaged mitochondria and ER‑stress sensors, priming them for recognition by SARs.
OPTN activation: TBK1 phosphorylates OPTN at Ser177, enhancing its affinity for ubiquitin and promoting oligomerization through its coiled‑coil domain. Oligomeric OPTN forms high‑avidity platforms that sequester LC3 more efficiently than monomeric p62.
Competitive advantage: Oligomeric OPTN outcompetes p62 for limited LC3‑II sites on nascent autophagosomes, particularly when OPTN expression is upregulated (as seen in prolonged TNF‑α exposure) [3].
Cargo rerouting: OPTN oligomers preferentially bind SEC62‑containing ER fragments via its ubiquitin‑associated domain, directing autophagosomes to engulf ER (ER‑phagy) while sparing mitochondria and aggregates.
Consequence: Persistent ER‑phagy depletes the biosynthetic ER membrane and chaperone reserve, attenuating secretory capacity and propagating proteotoxic stress—a hallmark of aging.

Testable Predictions

In aged mouse muscle, TBK1‑dependent p‑OPTN (Ser177) levels will correlate positively with SEC62‑LC3 co‑immunoprecipitation and negatively with mitophagy markers (e.g., PINK1‑Parkin ubiquitination).
Pharmacological inhibition of TBK1 or expression of a non‑oligomerizable OPTN mutant (Δcoiled‑coil) will shift the autophagy hierarchy back toward p62‑mediated mitophagy/aggrephagy, increase ER chaperone levels (BiP/GRP78), and improve grip strength.
Small‑molecule p62 agonists [5] will fail to rescue ER‑phagy unless OPTN oligomerization is concurrently suppressed, demonstrating the dominance of the OPTN‑SEC62 axis.

Experimental Approach

Generate a knock‑in mouse expressing OPTN‑S177A (non‑phosphorylatable) or OPTN‑ΔCC (oligomerization‑deficient) specifically in skeletal muscle using Cre‑loxP.
Monitor autophagy flux with mCherry‑GFP‑LC3 reporter and organelle‑specific reporters (mt‑Keima for mitochondria, GFP‑SEC62 for ER).
Assess muscle mass, strength, and transcriptome across lifespan.
Treat wild‑type aged mice with a TBK1 inhibitor (e.g., MRT67307) or a cell‑permeable peptide blocking OPTN oligomerization; compare to p62 agonist treatment.

If blocking OPTN oligomerization restores protective autophagy and delays functional decline, the hypothesis is supported; if ER‑phagy persists despite OPTN manipulation, the hypothesis is falsified.

[1] https://pmc.ncbi.nlm.nih.gov/articles/PMC4871809/ [2] https://pmc.ncbi.nlm.nih.gov/articles/PMC3971121/ [3] https://doi.org/10.1101/2025.05.06.650963 [4] https://doi.org/10.1038/s41467-020-15119-w [5] https://doi.org/10.1101/2025.05.27.656309

Hypothesis

Mechanistic Basis

Ubiquitin priming: Under inflammatory cues (e.g., TNF‑α), ubiquitin‑K63 chains accumulate on damaged mitochondria and ER‑stress sensors, priming them for recognition by SARs.

OPTN activation: TBK1 phosphorylates OPTN at Ser177, enhancing its affinity for ubiquitin and promoting oligomerization through its coiled‑coil domain. Oligomeric OPTN forms high‑avidity platforms that sequester LC3 more efficiently than monomeric p62.

Competitive advantage: Oligomeric OPTN outcompetes p62 for limited LC3‑II sites on nascent autophagosomes, particularly when OPTN expression is upregulated (as seen in prolonged TNF‑α exposure) [3].

Cargo rerouting: OPTN oligomers preferentially bind SEC62‑containing ER fragments via its ubiquitin‑associated domain, directing autophagosomes to engulf ER (ER‑phagy) while sparing mitochondria and aggregates.

Consequence: Persistent ER‑phagy depletes the biosynthetic ER membrane and chaperone reserve, attenuating secretory capacity and propagating proteotoxic stress—a hallmark of aging.

Testable Predictions

In aged mouse muscle, TBK1‑dependent p‑OPTN (Ser177) levels will correlate positively with SEC62‑LC3 co‑immunoprecipitation and negatively with mitophagy markers (e.g., PINK1‑Parkin ubiquitination).

Pharmacological inhibition of TBK1 or expression of a non‑oligomerizable OPTN mutant (Δcoiled‑coil) will shift the autophagy hierarchy back toward p62‑mediated mitophagy/aggrephagy, increase ER chaperone levels (BiP/GRP78), and improve grip strength.

Small‑molecule p62 agonists [5] will fail to rescue ER‑phagy unless OPTN oligomerization is concurrently suppressed, demonstrating the dominance of the OPTN‑SEC62 axis.

Experimental Approach

Generate a knock‑in mouse expressing OPTN‑S177A (non‑phosphorylatable) or OPTN‑ΔCC (oligomerization‑deficient) specifically in skeletal muscle using Cre‑loxP.

Monitor autophagy flux with mCherry‑GFP‑LC3 reporter and organelle‑specific reporters (mt‑Keima for mitochondria, GFP‑SEC62 for ER).

Assess muscle mass, strength, and transcriptome across lifespan.

Treat wild‑type aged mice with a TBK1 inhibitor (e.g., MRT67307) or a cell‑permeable peptide blocking OPTN oligomerization; compare to p62 agonist treatment.