Herneisen Alice L, Peters Michelle L, Smith Tyler A, Shortt Emily, Lourido Sebastian
Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA.
bioRxiv. 2024 May 2:2023.10.30.564746. doi: 10.1101/2023.10.30.564746.
Apicomplexan parasites balance proliferation, persistence, and spread in their metazoan hosts. AGC kinases, such as PKG, PKA, and the PDK1 ortholog SPARK, integrate environmental signals to toggle parasites between replicative and motile life stages. Recent studies have cataloged pathways downstream of apicomplexan PKG and PKA; however, less is known about the global integration of AGC kinase signaling cascades. Here, conditional genetics coupled to unbiased proteomics demonstrates that SPARK complexes with an elongin-like protein to regulate the stability of PKA and PKG in the model apicomplexan . Defects attributed to SPARK depletion develop after PKG and PKA are down-regulated. Parasites lacking SPARK differentiate into the chronic form of infection, which may arise from reduced activity of a coccidian-specific PKA ortholog. This work delineates the signaling topology of AGC kinases that together control transitions within the asexual cycle of this important family of parasites.
顶复门寄生虫在其后生动物宿主中平衡增殖、存活和传播。AGC激酶，如蛋白激酶G（PKG）、蛋白激酶A（PKA）以及PDK1直系同源物SPARK，整合环境信号以使寄生虫在复制性和运动性生命阶段之间转换。最近的研究已经梳理了顶复门PKG和PKA下游的信号通路；然而，对于AGC激酶信号级联的全局整合了解较少。在这里，条件遗传学与无偏蛋白质组学相结合表明，在模式顶复门生物中，SPARK与一种类延伸蛋白形成复合物以调节PKA和PKG的稳定性。归因于SPARK缺失的缺陷在PKG和PKA下调后出现。缺乏SPARK的寄生虫会分化为慢性感染形式，这可能是由于球虫特异性PKA直系同源物活性降低所致。这项工作描绘了AGC激酶的信号拓扑结构，这些激酶共同控制着这个重要寄生虫家族无性周期内的转变。
