白色念珠菌RHB1基因參與訊息傳導路徑及功能之研究

Study of the RHB1 gene-mediated signaling pathway and its functions in Candida albicans

曹長治(Chang-Chih Tsao)

指導教授 ： 藍忠昱

國立清華大學/生命科學院/分子與細胞生物研究所/碩士(2008年)

https://doi.org/10.6843/NTHU.2008.00268

摘要

白色念珠菌為一重要的真菌感染源，常見於院內感染之病例，以及免疫能力低落之病患。通常棲息於人類之口腔、喉部、大腸、皮膚及陰道等黏膜表面；等病人抵抗力機能衰退或受藥物副作用，即可侵入內部器官，引起溫和或嚴重的感染。Ras家族的小型G蛋白質(small G-protein)廣泛的在各種生物間被研究，包括Ras, Raf, Rho等等，都在細胞間的訊息傳導及功能上扮演著重要的角色。本研究著眼於一新發現的Ras家族小型G蛋白質，Rheb (Ras Homologue Enrich in Brain)在致病性真菌白色念珠菌(Candida albicans)中的同源基因RHB1所參與的訊息傳遞以及功能的探討。由於在另一致病性真菌燻煙色麴菌(Aspergillus fumigatus)中的同源基因已被證實與其致病能力相關，因此RHB1基因的研究也顯得有其重要性。為了進一步了解RHB1在白色念珠菌中所扮演的角色，本研究製造一缺乏RHB1基因的突變菌株，並比較其與正常野生菌株之差異。研究顯示RHB1可能參與了TOR激脢的訊息傳導路徑，並在其上游扮演活化因子的角色，並透過MEP2基因參與了白色念珠菌受到環境中氮源缺乏刺激而產生型態變化的機制。此外，RHB1也經由Mkc1激酶之訊息傳遞，參與細胞壁完整性的機制。最後，在使用老鼠的活體感染實驗中，RHB1也確實影響了白色念珠菌的致病能力。本研究顯示了小型G蛋白質在白色念珠菌中的訊息路徑及與環境因子之互動，同時也對白色念珠菌之致病能力及因子提供了嶄新的觀點。

關鍵字

白色念珠菌 ； 致病力 ； 小型G蛋白 ； HASH(0x1a687600) ； HASH(0x1a6876a0) ； HASH(0x1a687740)

並列摘要

The TOR (target of rapamycin) kinase signaling pathway plays an important role in a wide variety of cell functions. In mammals, fly and fission yeast, the TOR kinase is controlled by signal components, including Rheb, a new member of the small G-proteins of Ras superfamily, which has been identified in most of model organism and involved in many cell functions. Moreover, the Rheb homologue in the human fungal pathogen, Aspergillus fumigatus, is involved in the virulence of this pathogen. In this study, the Rheb homologues in the fungal pathogen Candida albicans, RHB1 was identified. To gain insight into the function of these genes, the deletion strains of RHB1 was generated. In comparisons of the mutant to wild type strains, RHB1 deletion mutant showed enhanced sensitivities to potent anti-TOR kinase drug rapamycin, suggesting RHB1 correlated and has positive effect in TOR-like pathway in C. albicans. Further studies indicated RHB1 is involved in yeast-hyphae transition which responded to nitrogen starvation via a sensor protein Mep2, the downstream target of TOR signaling pathway. Moreover, RHB1 is involved in cell wall integrity pathway and transmitted signals through TOR kinase and downstream MAP kinase, MKC1. Finally, RHB1 alters C. albicans virulence in a mouse model of systemic infection. Together, this study reveals a novel signaling pathway and provides insights to correlate environmental signaling and C. albicans pathogeneis.

並列關鍵字

Candida albicans ； RHEB ； RHB1 ； virulence ； cell wall integrity ； MEP2

參考文獻

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