Blood · 2023
Human genetic defects in SRP19 and SRPRA cause severe congenital neutropenia with distinctive proteome changes.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Linder Monika I, Mizoguchi Yoko, Hesse Sebastian, Csaba Gergely, Tatematsu Megumi, Łyszkiewicz Marcin, Ziȩtara Natalia, Jeske Tim, Hastreiter Maximilian, Rohlfs Meino, Liu Yanshan, Grabowski Piotr, Ahomaa Kaarin, Maier-Begandt Daniela, Schwestka Marko, Pazhakh Vahid, Isiaku Abdulsalam I, Briones Miranda Brenda, Blombery Piers, Saito Megumu K, Rusha Ejona, Alizadeh Zahra, Pourpak Zahra, Kobayashi Masao, Rezaei Nima, Unal Ekrem, Hauck Fabian, Drukker Micha, Walzog Barbara, Rappsilber Juri, Zimmer Ralf, Lieschke Graham J, Klein Christoph
Аннотация
The mechanisms of coordinated changes in proteome composition and their relevance for the differentiation of neutrophil granulocytes are not well studied. Here, we discover 2 novel human genetic defects in signal recognition particle receptor alpha (SRPRA) and SRP19, constituents of the mammalian cotranslational targeting machinery, and characterize their roles in neutrophil granulocyte differentiation. We systematically study the proteome of neutrophil granulocytes from patients with variants in the SRP genes, HAX1, and ELANE, and identify global as well as specific proteome aberrations. Using in vitro differentiation of human induced pluripotent stem cells and in vivo zebrafish models, we study the effects of SRP deficiency on neutrophil granulocyte development. In a heterologous cell-based inducible protein expression system, we validate the effects conferred by SRP dysfunction for selected proteins that we identified in our proteome screen. Thus, SRP-dependent protein processing, intracellular trafficking, and homeostasis are critically important for the differentiation of neutrophil granulocytes.