Abstract
The molecular mechanisms that control the biosynthetic trafficking, surface delivery, and degradation of TrkA receptor are essential for proper nerve growth factor (NGF) function, and remain poorly understood. Here, we identify Tetraspanin1 (Tspan1) as a critical regulator of TrkA signaling and neuronal differentiation induced by NGF. Tspan1 is expressed by developing TrkA-positive dorsal root ganglion (DRG) neurons and its downregulation in sensory neurons inhibits NGF-mediated axonal growth. In addition, our data demonstrate that Tspan1 forms a molecular complex with the immature form of TrkA localized in the endoplasmic reticulum (ER). Finally, knockdown of Tspan1 reduces the surface levels of TrkA by promoting its preferential sorting towards the autophagy/lysosomal degradation pathway. Together, these data establish a novel homeostatic role of Tspan1, coordinating the biosynthetic trafficking and degradation of TrkA, regardless the presence of NGF.
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Abbreviations
- CNX:
-
Calnexin
- DRG:
-
Dorsal root ganglia
- ER:
-
Endoplasmic reticulum
- Erk:
-
Extracellular signal-regulated kinase
- GDNF:
-
Glial cell line-derived neurotrophic factor
- Lamp1:
-
Lisosomal-associated membrane protein 1
- NGF:
-
Nerve growth factor
- PNS:
-
Peripheral nervous system
- P75NTR:
-
p75 neurotrophin receptor
- Ret:
-
Rearranged in transformation
- RTK:
-
Receptor tyrosine kinase
- TBP:
-
TATA-binding protein
- TEMs:
-
Tetraspanin-enriched microdomains
- TrkA:
-
Tropomyosin-related kinase A
- Tspan:
-
Tetraspanin
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Acknowledgements
We thank Dr. Marcal Vilar for TrkA-L213P construct, Dr. Michael G. Tomlinson for different Tspan constructs, Dr David Sabatini for Lamp1-RFP plasmid; Andrea Pecile and Manuel Ponce for animal care, Lic. Nerina Villalba and Dr. Sebastián Giusti for technical assistance, and Innova-T and UBATEC for research grant administration. This work was supported by the Argentine Agency for Promotion of Science and Technology (ANPCyT) PICT2015-3814, PICT2016-1512, PICT2017-4513. GP, FL, and TF were supported by an Independent Research Career Position from the Argentine Medical Research Council (CONICET). FFR, PAF, and APD were supported by a fellowship from CONICET.
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Conceived and designed the experiments: FFR, FL, and GP. Performed the experiments and statistical analysis: FFR, PAF, and AD. Analysis and interpretation of the data: FFR, TF, FL, and GP. Wrote the paper: GP.
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Ferrero Restelli, F., Fontanet, P.A., De Vincenti, A.P. et al. Tetraspanin1 promotes NGF signaling by controlling TrkA receptor proteostasis. Cell. Mol. Life Sci. 77, 2217–2233 (2020). https://doi.org/10.1007/s00018-019-03282-3
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DOI: https://doi.org/10.1007/s00018-019-03282-3