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Tetraspanin1 promotes NGF signaling by controlling TrkA receptor proteostasis

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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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Authors and Affiliations

  1. División de Neurobiología Molecular y Celular, Instituto de Biología Celular y Neurociencias (IBCN)-CONICET-UBA, Facultad de Medicina, University of Buenos Aires (UBA), CP1121, Buenos Aires, Argentina

    Facundo Ferrero Restelli, Paula Aldana Fontanet, Ana Paula De Vincenti, Fernanda Ledda & Gustavo Paratcha

  2. Laboratorio de Transporte Axonal y Enfermedades Neurodegenerativas, Instituto de Biología Celular y Neurociencias (IBCN)-CONICET-UBA, Facultad de Medicina, University of Buenos Aires (UBA), CP1121, Buenos Aires, Argentina

    Tomás Luis Falzone

  3. Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA), CONICET, Buenos Aires, Argentina

    Fernanda Ledda

Authors
  1. Facundo Ferrero Restelli
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  2. Paula Aldana Fontanet
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  3. Ana Paula De Vincenti
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  4. Tomás Luis Falzone
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  5. Fernanda Ledda
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  6. Gustavo Paratcha
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Contributions

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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Correspondence to Gustavo Paratcha.

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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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