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Published on: December 6, 2019
Sorting Nexin 11 Regulates Lysosomal Degradation of Plasma Membrane TRPV3
Caiyue Li1, Wenbo Ma1, Shikui Yin1
1Key Laboratory of Regenerative Biology, Chinese Academy of Sciences and Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Abstract:
The trafficking of ion channels to/from the plasma membrane is considered an important mechanism for cellular activity and an interesting approach for disease therapies. The transient receptor potential vanilloid 3 (TRPV3) ion channel is widely expressed in skin keratinocytes, and its trafficking mechanism to/from the plasma membrane is unknown. Here, we report that the vesicular trafficking protein sorting nexin 11 (SNX11) downregulates the level of the TRPV3 plasma membrane protein. Overexpression of SNX11 causes a decrease in the level of TRPV3 current and TRPV3 plasma membrane protein in TRPV3-transfected HEK293T cells. Subcellular localizations and western blots indicate that SNX11 interacts with TRPV3 and targets it to lysosomes for degradation, which is blocked by the lysosomal inhibitors chloroquine and leupeptin. Both TRPV3 and SNX11 are highly expressed in HaCaT cells. We show that TRPV3 agonists-activated Ca(2+) influxes and the level of native TRPV3 total protein in HaCaT cells are decreased by overexpression of SNX11 and increased by knockdown of SNX11. Our findings reveal that SNX11 promotes the trafficking of TRPV3 from the plasma membrane to lysosomes for degradation via protein-protein interactions, which demonstrates a previously unknown function of SNX11 as a regulator of TRPV3 trafficking from the plasma membrane to lysosomes.
Insights
Sorting nexin 11 (SNX11) protein reduces transient receptor potential vanilloid 3 (TRPV3) ion channels at the cell surface. SNX11 targets TRPV3 for lysosomal degradation, revealing a new regulatory role in skin cells.
Area of Science:
- Cell Biology
- Molecular Biology
- Physiology
Background:
- Ion channel trafficking to the plasma membrane regulates cellular functions and offers therapeutic targets.
- The trafficking mechanisms of transient receptor potential vanilloid 3 (TRPV3) channels, prevalent in skin keratinocytes, remain largely uncharacterized.
Purpose of the Study:
- To elucidate the role of sorting nexin 11 (SNX11) in regulating TRPV3 ion channel plasma membrane levels and function.
Main Methods:
- Utilized TRPV3-transfected HEK293T cells and HaCaT cells.
- Investigated protein-protein interactions using subcellular localization and Western blotting.
- Assessed TRPV3 current and Ca(2+) influx.
- Employed lysosomal inhibitors (chloroquine, leupeptin), SNX11 overexpression, and SNX11 knockdown.
Main Results:
- SNX11 overexpression decreased TRPV3 plasma membrane levels and TRPV3-mediated currents in HEK293T cells.
- SNX11 directly interacts with TRPV3 and targets it for lysosomal degradation, a process inhibited by chloroquine and leupeptin.
- In HaCaT cells, SNX11 overexpression reduced TRPV3 agonist-activated Ca(2+) influx and total TRPV3 protein, while SNX11 knockdown increased them.
Conclusions:
- SNX11 promotes the lysosomal degradation of TRPV3 channels via protein-protein interactions.
- This study identifies a novel function for SNX11 in regulating TRPV3 trafficking from the plasma membrane to lysosomes.
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