Department of Life Sciences, Imperial College, London, United Kingdom.
School of Biological Sciences, University of California, San Diego, La Jolla, California, United States of America.
PLoS Biol. 2024 Mar 11;22(3):e3002543. doi: 10.1371/journal.pbio.3002543. eCollection 2024 Mar.
Protein quality control pathways play important roles in resistance against pathogen infection. For example, the conserved transcription factor SKN-1/NRF up-regulates proteostasis capacity after blockade of the proteasome and also promotes resistance against bacterial infection in the nematode Caenorhabditis elegans. SKN-1/NRF has 3 isoforms, and the SKN-1A/NRF1 isoform, in particular, regulates proteasomal gene expression upon proteasome dysfunction as part of a conserved bounce-back response. We report here that, in contrast to the previously reported role of SKN-1 in promoting resistance against bacterial infection, loss-of-function mutants in skn-1a and its activating enzymes ddi-1 and png-1 show constitutive expression of immune response programs against natural eukaryotic pathogens of C. elegans. These programs are the oomycete recognition response (ORR), which promotes resistance against oomycetes that infect through the epidermis, and the intracellular pathogen response (IPR), which promotes resistance against intestine-infecting microsporidia. Consequently, skn-1a mutants show increased resistance to both oomycete and microsporidia infections. We also report that almost all ORR/IPR genes induced in common between these programs are regulated by the proteasome and interestingly, specific ORR/IPR genes can be induced in distinct tissues depending on the exact trigger. Furthermore, we show that increasing proteasome function significantly reduces oomycete-mediated induction of multiple ORR markers. Altogether, our findings demonstrate that proteasome regulation keeps innate immune responses in check in a tissue-specific manner against natural eukaryotic pathogens of the C. elegans epidermis and intestine.
蛋白质质量控制途径在抵抗病原体感染方面发挥着重要作用。例如，保守的转录因子 SKN-1/NRF 在蛋白酶体阻断后上调蛋白质稳态能力，并且还促进线虫秀丽隐杆线虫中对细菌感染的抗性。SKN-1/NRF 有 3 种同工型，特别是 SKN-1A/NRF1 同工型，在蛋白酶体功能障碍时调节蛋白酶体基因表达，作为保守反弹反应的一部分。我们在这里报告说，与 SKN-1 先前报道的促进抵抗细菌感染的作用相反，skn-1a 及其激活酶 ddi-1 和 png-1 的功能丧失突变体表现出针对秀丽隐杆线虫天然真核病原体的固有免疫反应程序的组成型表达。这些程序是卵菌识别反应 (ORR)，它促进对通过表皮感染的卵菌的抗性，以及细胞内病原体反应 (IPR)，它促进对感染肠道的微孢子虫的抗性。因此，skn-1a 突变体对卵菌和微孢子虫感染的抗性均增加。我们还报告说，这两个程序之间共同诱导的几乎所有 ORR/IPR 基因都受到蛋白酶体的调节，有趣的是，特定的 ORR/IPR 基因可以根据确切的触发在不同的组织中诱导。此外，我们表明，增加蛋白酶体功能可显著降低卵菌介导的多个 ORR 标记物的诱导。总之，我们的研究结果表明，蛋白酶体调节以组织特异性的方式对秀丽隐杆线虫表皮和肠道的天然真核病原体保持先天免疫反应的控制。
