Kidney Week

Abstract: TH-OR058

Mitigation of Cystogenesis in ADPKD: Role of PC1-interacting IP1 Deficiency in Modulation of LC3-Dependent Autophagy

Session Information

• Genetic Diseases with a Focus on ADPKD Mechanisms, Models, and Medicines
  October 22, 2026 | Location: Mile High Ballroom 4D, Convention Center
  Abstract Time: 05:00 PM - 05:10 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)

Authors

• Zhang, Yilin, Harvard Medical School, Boston, Massachusetts, United States

Yilin Zhang, MD, PhD

• Yao, Gang, Harvard Medical School, Boston, Massachusetts, United States

Gang Yao, MD, PhD

• Zahir, Danish, Harvard Medical School, Boston, Massachusetts, United States

Danish Zahir

• Ayub, Armaghan, Harvard Medical School, Boston, Massachusetts, United States

Armaghan Ayub, MD

• Shahid, Hafsa, Harvard Medical School, Boston, Massachusetts, United States

Hafsa Shahid, MD, MBBS

• Mohammadi, Ario, Harvard Medical School, Boston, Massachusetts, United States

Ario Mohammadi, MD

• Haider, Salar, Harvard Medical School, Boston, Massachusetts, United States

Salar Haider, MD

• Zhou, Jing, Harvard Medical School, Boston, Massachusetts, United States

Jing Zhou, MD, PhD, FASN

Background

ADPKD is driven by loss of polycystin-1 (PC1), yet how PC1 deficiency disrupts autophagy and epithelial homeostasis remains unclear.

Methods

We generated inducible Pkd1 and/or IP1 mutant mice via tamoxifen injection at 3 wks of age. Cell death pathways were identified by human snRNA-seq and mouse proteomic. Protein interactions predicted by AlphaFold3 were confirmed by co-IP.

Results

We analyzed human ADPKD snRNA-seq and found that IP1 is significantly upregulated in distal tubular cells, further supported by increased protein abundance and enhanced expression in the thick ascending limb and collecting duct. Genetic deletion of IP1 markedly attenuates cystogenesis in Pkd1 SKO mice, with reduced epithelial proliferation and apoptosis, establishing a pathogenic role for IP1.
Integrated proteomic and phosphoproteomic showed significant autophagy dysregulation in Pkd1-deficient kidneys. Notably, IP1 acts as a negative regulator of autophagy, as its deletion restores Pkd1 loss–induced defects in autophagy signalling. Consistently, upstream autophagy-regulating pathways, including mTOR and Wnt, together with autophagy related proteins, are disrupted in Pkd1 SKO and rescued in Pkd1/IP1 DKO mice, indicating recovery of autophagic homeostasis.
Mechanistically, IP1 forms a complex with PC1 and LC3. AI–based structural modeling (pilot AlphaFold3) combined with docking showed that IP1 contains an LC3-interacting region, with PC1 maintaining a close IP1–LC3 distance (~2.8 Å) that is disrupted upon PC1 loss (~12.9 Å), predicting impaired binding. Co-IP confirmed reduced IP1–LC3 interaction in human ADPKD cells and primary Pkd1 SKO tubular cells compared to normal RCTEC and WT cells. Notably, BafA1, which blocks autophagosome–lysosome fusion, amplified autophagic flux markers and showed clear differences between DKO and Pkd1 SKO mice. These findings suggested that disruption of the IP1–LC3 interaction upon PC1 loss contributes to autophagy defect, while IP1 deficiency restores autophagic flux. Migration assay showed that IP1 localized to leading edge with organized actin in normal cells but is retained in the cell body in ADPKD cells, and its loss impairs migration, indicating a role in cytoskeletal dynamics linked to autophagy.

Conclusion

Collectively, our work identified defective autophagic maturation as a pathogenic driver in ADPKD, highlighting IP1 as a potential therapeutic target.