Invited Speaker 11th International Symposium on Autophagy 2025

A novel Rubicon interactor links Rubicon to TRPML1-dependent Ca²⁺ regulation of autophagy (130521)

Fangze Duan 1 , Tatsuya Kaminishi 1 , Keisuke Tabata 2 , Ryosuke Kawagoe 3 , Shuhei Nakamura 4 , Tamotsu Yoshimori 1 5 , Maho Hamasaki 1 6
  1. Graduate School of Medicine, University of Osaka, Osaka, Japan
  2. Department of Physiology, Graduate School of Medicine, Juntendo University, Tokyo, Japan
  3. Japan Tobacco Inc., Central Pharmaceutical Research Institute, Osaka, Japan
  4. Nara Medical University, Nara, Japan
  5. Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka, Japan
  6. Laboratory of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan

Autophagy is dynamically regulated by nutrient status and intracellular signaling. Rubicon is a well-known negative regulator of autophagy, but the mechanism underlying its inhibition has remained unclear. Here we identify a novel Rubicon interactor that colocalizes with lysosomes and positively influences autophagic flux. Importantly, Rubicon depletion triggers lysosomal Ca²⁺ transients, which are required for autophagic activation through the TRPML1 channel. Disrupting either TRPML1 function or Ca²⁺ availability abolishes this response. These findings indicate that Rubicon and its novel interactor converge on a TRPML1-dependent Ca²⁺ signaling step shared with starvation-induced autophagy.