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O-linked glycan-dependent gating of TPC2 controls lysosomal excitability and organelle remodeling

Alice Lin1, Neng-Yu Lin2, Marco Keller3

  • 1Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.

Nature Communications
|June 10, 2026
PubMed

Insights

Mucin-type O-linked glycosylation on TPC2 acts as a brake. Removing these glycans enhances TPC2 channel activity, impacting lysosomal function and cell migration in cancer.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Two-pore channel 2 (TPC2) is a lysosomal cation channel crucial for cellular processes.
  • TPC2 dysfunction is implicated in viral infections, neurodegenerative diseases, and cancer.

Purpose of the Study:

  • To investigate the role of glycosylation in regulating TPC2 channel activity.
  • To understand how TPC2 gating affects lysosomal function and cell behavior.

Main Methods:

  • Structure-guided mutagenesis and genetic modification of TPC2.
  • Lysosomal patch-clamp recordings and calcium nanodomain imaging.
  • Molecular dynamics simulations and small-molecule modulation.

Main Results:

  • Identified mucin-type O-linked glycosylation at Ser612 and Ser613 as a TPC2 gating brake.
  • Glycan removal (genetic, enzymatic, or pharmacological) enhances TPC2 activity, leading to lysosomal tubulation and increased vesicle mobility.
  • Glycan-deficient TPC2 promotes cancer cell migration, reversible with inhibitors like tetrandrine and SC-3.

Conclusions:

  • Luminal glycosylation is a key post-translational regulator of TPC2 gating.
  • TPC2 activity influences lysosomal architecture and disease-relevant cell behaviors, including cancer cell migration.

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