A marine sponge-derived lectin reveals hidden pathway for thrombopoietin receptor activation

Hiromi Watari, Hiromu Kageyama, Nami Masubuchi, Hiroya Nakajima, Kako Onodera, Pamela J. Focia, Takumi Oshiro, Takashi Matsui, Yoshio Kodera, Tomohisa Ogawa, Takeshi Yokoyama, Makoto Hirayama, Kanji Hori, Douglas M. Freymann, Misa Imai, Norio Komatsu, Marito Araki (), Yoshikazu Tanaka () and Ryuichi Sakai ()
Additional contact information
Hiromi Watari: Hokkaido University
Hiromu Kageyama: Tohoku University
Nami Masubuchi: Juntendo University Graduate School of Medicine
Hiroya Nakajima: Hokkaido University
Kako Onodera: Tohoku University
Pamela J. Focia: Northwestern University
Takumi Oshiro: Kitasato University
Takashi Matsui: Kitasato University
Yoshio Kodera: Kitasato University
Tomohisa Ogawa: Tohoku University
Takeshi Yokoyama: Tohoku University
Makoto Hirayama: Hiroshima University
Kanji Hori: Hiroshima University
Douglas M. Freymann: Northwestern University
Misa Imai: Juntendo University Graduate School of Medicine
Norio Komatsu: Juntendo University Graduate School of Medicine
Marito Araki: Juntendo University Graduate School of Medicine
Yoshikazu Tanaka: Tohoku University
Ryuichi Sakai: Hokkaido University

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract N-glycan-mediated activation of the thrombopoietin receptor (MPL) under pathological conditions has been implicated in myeloproliferative neoplasms induced by mutant calreticulin, which forms an endogenous receptor-agonist complex that traffics to the cell surface and constitutively activates the receptor. However, the molecular basis for this mechanism is elusive because oncogenic activation occurs only in the cell-intrinsic complex and is thus cannot be replicated with external agonists. Here, we describe the structure and function of a marine sponge-derived MPL agonist, thrombocorticin (ThC), a homodimerized lectin with calcium-dependent fucose-binding properties. In-depth characterization of lectin-induced activation showed that, similar to oncogenic activation, sugar chain-mediated activation persists due to limited receptor internalization. The strong synergy between ThC and thrombopoietin suggests that ThC catalyzes the formation of receptor dimers on the cell surface. Overall, the existence of sugar-mediated MPL activation, in which the mode of activation is different from the original ligand, suggests that receptor activation is unpredictably diverse in living organisms.

Date: 2022
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DOI: 10.1038/s41467-022-34921-2

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