Specificity of Membrane-Associated J-Domain Protein, Caj1, in Amphotericin B Tolerance in Budding Yeast,Molecular Microbiology

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Specificity of Membrane-Associated J-Domain Protein, Caj1, in Amphotericin B Tolerance in Budding Yeast
Molecular Microbiology ( IF 2.6 ) Pub Date : 2024-09-17 , DOI: 10.1111/mmi.15318
Preeti Sagarika ₁ , Neha Dobriyal ₂ , Pakirisamy Deepsika ₁ , Avanti Vairagkar ₃ , Ankita Das ₄ , Chandan Sahi ₁

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Hsp70:J-domain protein (JDP) machineries play pivotal roles in maintaining cellular proteostasis and governing various aspects of fungal physiology. While Hsp70 is known for its involvement in conferring tolerance to diverse antifungal drugs, the specific contribution of JDPs remains unclear. In this study, we examined the sensitivity of cytosolic JDP deletion strains of budding yeast to amphotericin B (AmB), a polyene antifungal agent widely utilized in fungal disease treatment due to its ability to disrupt the fungal plasma membrane (PM). Deleting Caj1, a PM-associated class II JDP, heightened susceptibility to AmB, and the protection conferred by Caj1 against AmB necessitated both its N-terminal J-domain and C-terminal lipid binding domain. Moreover, Caj1 deficiency compromised PM integrity as evidenced by increased phosphate efflux and exacerbated AmB sensitivity, particularly at elevated temperatures. Notably, phytosphingosine (PHS) addition as well as overexpression of PMP3, a positive PM integrity regulator, significantly rescued AmB sensitivity of caj1Δ cells. Our results align with the notion that Caj1 associates with the PM and cooperates with Hsp70 to regulate PM proteostasis, thereby influencing PM integrity in budding yeast. Loss of Caj1 function at the PM compromises PM protein quality control, thereby rendering yeast cells more susceptible to AmB.

中文翻译：

膜相关 J 结构域蛋白 (Caj1) 在出芽酵母中两性霉素 B 耐受性中的特异性

Hsp70:J 结构域蛋白 (JDP) 机制在维持细胞蛋白质稳态和控制真菌生理学的各个方面发挥着关键作用。虽然 Hsp70 因其参与赋予多种抗真菌药物耐受性而闻名，但 JDP 的具体贡献仍不清楚。在这项研究中，我们检测了芽殖酵母胞质 JDP 缺失菌株对两性霉素 B (AmB) 的敏感性，两性霉素 B 是一种多烯抗真菌剂，因其破坏真菌质膜 (PM) 的能力而广泛用于真菌疾病治疗。删除 Caj1（一种与 PM 相关的 II 类 JDP）会增加对 AmB 的敏感性，并且 Caj1 赋予的针对 AmB 的保护需要其 N 端 J 结构域和 C 端脂质结合结构域。此外，Caj1 缺乏会损害 PM 完整性，磷酸盐流出量增加和 AmB 敏感性加剧（特别是在高温下）证明了这一点。值得注意的是，植物鞘氨醇 (PHS) 的添加以及 PMP3（一种 PM 完整性正调节剂）的过度表达，显着挽救了 caj1Δ 细胞的 AmB 敏感性。我们的结果与 Caj1 与 PM 相关联并与 Hsp70 合作调节 PM 蛋白质稳态，从而影响芽殖酵母中 PM 完整性的观点一致。 PM 处 Caj1 功能的丧失会损害 PM 蛋白质的质量控制，从而使酵母细胞更容易受到 AmB 的影响。

更新日期：2024-09-17

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