Madeo Frank, Durchschlag Michael, Kepp Oliver, Panaretakis Theocharis, Zitvogel Laurence, Fröhlich Kai-Uwe, Kroemer Guido
Institute of Molecular Biosciences, University of Graz, Graz, Austria.
Cell Cycle. 2009 Feb 15;8(4):639-42. doi: 10.4161/cc.8.4.7794. Epub 2009 Feb 8.
The pre-apoptotic exposure of calreticulin (CRT) on the cell surface determines the efficient engulfment of mouse or human tumor cells by antigen-presenting dendritic cells. CRT exposure is rapidly induced by anthracyclins and ionizing irradiation and follows a complex signal transduction pathway that is interrupted by depletion of PERK, caspase-8, BAP31, Bax, Bak or SNAREs, as well as by knock-in mutation of eIF2alpha (to make it non-phosphorylable by PERK) or BAP31 (to render it uncleavable by caspase-8). Here, we show that yeast (Saccharomyces cerevisiae) can expose the CRT orthologue CNE1 on the surface in response to cell death induced by the anthracylin mitoxantrone (MTX). This MTX-triggered CNE1 translocation is abolished by knockout of the yeast orthologues of PERK (Gcn2), BAP31 (Yet3) and SNAREs (Nyv1, Sso1). Altogether, our data point to the existence of an ancestral and cell death-related CRT exposure pathway with conserved elements shared between unicellular fungi and mammals.
钙网蛋白（CRT）在细胞表面的促凋亡暴露决定了抗原呈递树突状细胞对小鼠或人类肿瘤细胞的有效吞噬。蒽环类药物和电离辐射可迅速诱导CRT暴露，其遵循一条复杂的信号转导途径，该途径会因PERK、半胱天冬酶-8、BAP31、Bax、Bak或SNAREs的缺失，以及eIF2α（使其不能被PERK磷酸化）或BAP31（使其不能被半胱天冬酶-8切割）的敲入突变而中断。在此，我们表明酵母（酿酒酵母）可响应蒽环类米托蒽醌（MTX）诱导的细胞死亡，将CRT同源物CNE1暴露于表面。这种MTX触发的CNE1易位可通过敲除酵母中PERK（Gcn2）、BAP31（Yet3）和SNAREs（Nyv1、Sso1）的同源物而被消除。总之，我们的数据表明存在一种与细胞死亡相关的祖先CRT暴露途径，其具有单细胞真菌和哺乳动物共有的保守元件。
