臺灣博碩士論文加值系統

真菌類的侵入性生長會影響其致病能力，其調控機制在過去已被研究的相當廣泛。Bud2p可以幫助Bud1p/Rsr1p之鳥糞嘌呤核苷三磷酸水解能力，Bud2p在過去的研究中指出會參與在酵母菌出芽生殖及侵入性生長的過程中，但是詳細的分子機制目前還尚未了解。本研究指出：在酵母菌侵入性生長的過程中Arf3p可以調控Bud2p的活性。我們發現Arf3p藉由直接作用於Bud2p的胺基端來促進其酵素活性，透過遺傳學及生化分析也發現Bud1p的活化態及不活化態可以影響酵母菌侵入性生長，且當細胞中缺乏Arf3p或是Bud2p都會讓細胞中累積過多的活化態Bud1p。此外，我們也發現當葡萄糖缺乏所引發的酵母菌侵入性生長中，會增加活化態Arf3p，且此過程與其鳥糞嘌呤核苷酸交換因子Yel1p無關。因此我們提出一個機制，那就是當酵母菌遭遇到葡萄糖缺乏時，其會促進Arf3p活化，並會與Bud2p直接作用來調控Bud2p對於提升Bud1p之鳥糞嘌呤核苷三磷酸水解能力，進而影響酵母菌的侵入性生長。

The regulation and signaling pathways involved in the invasive growth of yeast have been studied extensively because of their general applicability to fungal pathogenesis. Bud2p, which functions as a GTPase-activating protein (GAP) for Bud1p/Rsr1p, is required for appropriate budding patterns and filamentous growth. However, the regulatory mechanisms leading to Bud2p activation are poorly understood. In this study, we report that Arf3p acts as a regulator of Bud2p activation during invasive growth. Arf3p binds directly to the N-terminal region of Bud2p and promotes its GAP activity both in vitro and in vivo. Genetic analysis shows that deletion of BUD1 suppresses the defect of invasive growth in arf3 or bud2 cells. Lack of Arf3p, like that of Bud2p, causes the intracellular accumulation of Bud1p-GTP. The Arf3p-Bud2p interaction is important for invasive growth and facilitates the Bud2p-Bud1p association in vivo. Finally, we show that under glucose depletion-induced invasion conditions in yeast, more Arf3p is activated to the GTP-bound state and the activation is independent of Arf3p guanine nucleotide-exchange factor (GEF) Yel1p. Thus, we demonstrate that a novel spatial activation of Arf3p plays a role in regulating Bud2p activation during glucose-depletion-induced invasive growth.

摘要……………………………………………………………………………………4
Abstract………………………………………………………………………………5
Abbreviations…………………………………………………………………………6
Chapter I. Literature Review…………………………………………………………7
1. Small GTP-binding Proteins…………………………………………………7
2. ADP-ribosylation Factors……………………………………………………10
3. Cell Polarity…………………………………………………………………16
Chapter II. Arf3p GTPase is a key regulator of Bud2p activation for haploid yeast invasive growth………………………………………………………………………26
1. Introduction…………………………………………………………………27
2. Results………………………………………………………………………28
3. Discussion……………………………………………………………………37
4. Materials and Methods………………………………………………………40
Tables…………………………………………………………………………………45
Table 1. Yeast strains used in this study…………………………………………45
Table 2. Plasmids used in this study…………………………………………46
Figures………………………………………………………………………………48
Figure 1. Arf3p is required for yeast invasive growth…………………………48
Figure 2. Arf3p specifically and directly interacts with Bud2p………………49
Figure 3. Arf3p associates with Bud2p in vivo…………………………………50
Figure 4. Schematic representation of the various constructs containing the BUD2 truncation mutants……………………………………………51
Figure 5. Arf3p interacts directly with the N-terminal region of Bud2p in a GTP-dependent manner………………………………………………52
Figure 6. Arf3p-GTP specifically interacts with the N-terminus of Bud2p in vitro…………………………………………………………………53
Figure 7. Bud2p interacts with Arf3pQ71L via the N-terminal region…………54
Figure 8. Bud2p-dN40 dissociates from Arf3p in vivo…………………………55
Figure 9. The N-terminus of Arf3p interacts with Bud2p………………………56
Figure 10. Alignment of Arf3p with other ARF protein family members………57
Figure 11. Polarization to daughter cell membrane and heavy membrane enrichment of Arf3p-GFP, Arf3pL23V-GFP, and Arf3pI33V-GFP……58
Figure 12. Isoleucine 33 of Arf3p is essential for the interaction of Arf3p with Bud2p………………………………………………………………59
Figure 13. Both Arf3pL23V and Arf3pI33V interact with Ye1lp and Afi1p………60
Figure 14. Arf3p and Bud2p independently localize to the bud neck…………61
Figure 15. Arf3p interacts with Bud2p to regulate yeast invasive growth……62
Figure 16. Bud2p-dN40 localizes to the bud neck……………………………63
Figure 17. The budding pattern seen with Bud2p-dN40 expression in bud2
Figure 18. Arf3p interacts with Bud2p to regulate yeast invasive growth……65
Figure 19. Yeast invasion is not altered by disruption of BUD1 or BUD5……66
Figure 20. Overexpression of active forms of Bud1p results in loss of agar invasion……………………………………………………………67
Figure 21. Depletion of BUD1 suppresses the invasive growth defect of arf3 and bud2 cells……………………………………………………68
Figure 22. Accumulation of Bud1p-GTP prevents yeast invasive growth……69
Figure 23. L681A and R682Q mutations in Bud2p (Bud2pAQ) cause defects in GAP activity………………………………………………………70
Figure 24. Bud2p GAP activity, which stimulates Bud1p-GTP hydrolysis, is required for both polarity establishment and yeast invasive growth………………………………………………………………71
Figure 25. GST-Cdc42-GDP specifically pulls down Bud1pG12V………………72
Figure 26. Elevated Bud1p-GTP levels were detected in arf3 and bud2 mutant cells…………………………………………………………………73
Figure 27. Bud2p interacts with Arf3p to enhance GAP activity leading to Bud1p-GTP hydrolysis in vivo……………………………………74
Figure 28. Interaction of Arf3p and Bud2p promotes Bud2p GAP activity leading to Bud1p GTP hydrolysis…………………………………………75
Figure 29. Arf3p facilitates the Bud2p-Bud1p association in vivo……………76
Figure 30. Arf3p is required for yeast invasive growth in response to glucose depletion……………………………………………………………77
Figure 31. Arf3p is activated by glucose depletion……………………………78
Figure 32. Arf3p and Bud2p independently polarize to the bud tip in response to glucose depletion……………………………………………………79
Figure 33. Glucose depletion induces Arf3p activation to promote Bud1p-GTP hydrolysis…………………………………………………………80
Figure 34. Yel1p is not required for agar invasion……………………………81
Figure 35. Arf3p associates with Bud2p in yel1 cells…………………………82
Figure 36. Disruption of YEL1 in yeast cells shows signals that polarize Arf3p-GFP to the bud tip in the absence of glucose………………83
Figure 37. Active forms of Arf3p are elevated in yel1 cells upon glucose depletion……………………………………………………………84
Figure 38. Gea1p, Gea2p, and Syt1p are not required for yeast invasive growth………………………………………………………………85
Figure 39. A model for the roles of Arf3p in budding polarity and yeast invasion……………………………………………………………86
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