PI(3,5)P2 Controls Membrane Traffic by Direct Activation of Mucolipin Ca2+ Release Channels in the Endolysosome

By Xian-Ping Dong, Dongbiao Shen, Xiang Wang, Taylor F. Dawson, Xinran Li, Qi Zhang, Xi-ping Cheng, Yanling Zhang, L. Weisman, M. Delling and 1 more. Nature Communications, 2010

615 citations recorded by the source corpus.

Membrane fusion and fission in intracellular trafficking is controlled by both intraluminal Ca2+ release and phosphoinositide signaling. However, the molecular identities of the Ca2+ release channels and the target proteins of phosphoinositides are elusive. Here, by direct patch-clamping of the endolysosomal membrane, we report that PI(3,5)P2, an endolysosome-specific phosphoinositide, binds and activates endolysosome-localized mucolipin TRP (TRPML) channels with specificity and potency. Both PI(3,5)P2-deficient cells and cells that lack TRPML1 exhibited enlarged endolysosomes/vacuoles and trafficking defects in the late endocytic pathway. We find that the enlarged vacuole phenotype observed in PI(3,5)P2-deficient mouse fibroblasts is suppressed by overexpression of TRPML1. Notably, this PI(3,5)P2-dependent regulation of TRPML1 is evolutionarily conserved. In budding yeast, hyperosmotic stress induces Ca2+ release from the vacuole. Here, we show that this release requires both PI(3,5)P2 production and a yeast functional TRPML homolog. We propose that TRPMLs regulate membrane trafficking by transducing information about PI(3,5)P2 levels into changes in juxtaorganellar Ca2+, thereby triggering membrane fusion/fission events.

Subfields: Physiology, Plant Science, Sensory Systems

View Paper: https://www.semanticscholar.org/paper/3afe0d39edff0a972eeccbe20d0b5a4c5da0e5c5

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Physiology

1. Jie Zheng
2. T. Balla
3. Ari Helenius
4. Jatta Huotari
5. Dejian Ren
6. Haoxing Xu
7. M. Trudeau

In Plant Science

1. T. Balla
2. Ari Helenius

In Sensory Systems

1. Jie Zheng
2. T. Balla
3. M. Trudeau

Citations in the corpus

• Endosome maturation (2011, background): “Ca2þ is known to have an important regulatory function in homotypic and heterotypic fusions of LEs and lysosomes/vacuoles as well as in reformation of lysosomes from endolysosomes (Luzio et al, 2007a).”
• Phosphoinositides: tiny lipids with giant impact on cell regulation. (2013, background): “Another group of effectors of PtdIns(3,5)P2 was recently identified as the mammalian TRPML proteins or mucolipins and their yeast homolog, Yvc1/TRPY1 (371).”
• Lysosomal Physiology (2015, background): “Ca2+-permeant, nonselective cation channels have been recorded in the lysosomes of most mammalian cell types, including fibroblasts, macrophages, pancreatic cells, and skeletal muscle cells (23, 24, 34, 68).”
• Handbook of ion channels (2015, background): “Under the wholeendolysosome configuration, most of the pore properties of vacuolar TRPMLs, such as the I–V relationship and ionic selectivity, resemble those of the PM-localized Va mutants (12,13).”