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<p>The maintenance of the haematopoietic stem cells and the production of platelets thereof is acutely dependent upon the thrombopoietin receptor (TpoR). TpoR dimerizes in the presence of its ligand thrombopoietin leading to the activation of downstream JAK2-STAT signalling. Alternatively, the receptor dimerizes in the presence of activating mutations of JAK2 (JAK2 V617F), calreticulin or TpoR leading to myeloproliferation. These effects are dependent upon the surface expression of the receptor. TpoR is secreted through the Golgi-dependent pathway. Although, an unconventional autophagosome-lysosome mediated traffic has been postulated; questions remained whether the observed lysosomal localization was indicative of degradation or secretion. We fused the pH-sensitive FRET pair of TOLLES-YPet with TpoR (SRAI-TpoR) that showed FRET quenching at low pH environment of lysosomes. Using this construct, we demonstrated the presence of quenched SRAI-TpoR on the cell surface indicating that TpoR could indeed be secreted through low pH compartments. We further demonstrated that the lysosome-autophagosome-mediated secretion of TpoR was promoted by JAK2 V617F mutation, partially utilized by TpoR W515L but abrogated by calreticulin mutations. Finally, we showed that the lysosome-autophagosome mediated secretion was dependent upon Rab1A. Our study conclusively showed the unconventional traffic of TpoR and its modulation by the driver mutations causing myeloproliferation.</p>

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Autophagosome-lysosome mediated secretion of the thrombopoietin receptor is modulated by distinct driver mutations of myeloproliferative neoplasm

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月3日

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  • Shayeri Chowdhury,
  • Saurabh Shrivastva,
  • Aditi Singh,
  • Farmaanullah Ansari,
  • Saadia Naseer,
  • Anita Roy

摘要

The maintenance of the haematopoietic stem cells and the production of platelets thereof is acutely dependent upon the thrombopoietin receptor (TpoR). TpoR dimerizes in the presence of its ligand thrombopoietin leading to the activation of downstream JAK2-STAT signalling. Alternatively, the receptor dimerizes in the presence of activating mutations of JAK2 (JAK2 V617F), calreticulin or TpoR leading to myeloproliferation. These effects are dependent upon the surface expression of the receptor. TpoR is secreted through the Golgi-dependent pathway. Although, an unconventional autophagosome-lysosome mediated traffic has been postulated; questions remained whether the observed lysosomal localization was indicative of degradation or secretion. We fused the pH-sensitive FRET pair of TOLLES-YPet with TpoR (SRAI-TpoR) that showed FRET quenching at low pH environment of lysosomes. Using this construct, we demonstrated the presence of quenched SRAI-TpoR on the cell surface indicating that TpoR could indeed be secreted through low pH compartments. We further demonstrated that the lysosome-autophagosome-mediated secretion of TpoR was promoted by JAK2 V617F mutation, partially utilized by TpoR W515L but abrogated by calreticulin mutations. Finally, we showed that the lysosome-autophagosome mediated secretion was dependent upon Rab1A. Our study conclusively showed the unconventional traffic of TpoR and its modulation by the driver mutations causing myeloproliferation.