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SNF3 as High Affinity Glucose Sensor and Its Function in Supporting the Viability of Candida glabrata under Glucose-Limited Environment.

Ng TS, Chew SY, Rangasamy P, Mohd Desa MN, Sandai D, Chong PP, Than LT - Front Microbiol (2015)

Bottom Line: Candida glabrata is an emerging human fungal pathogen that has efficacious nutrient sensing and responsiveness ability.It can be seen through its ability to thrive in diverse range of nutrient limited-human anatomical sites.The deletion of SNF3 also resulted in the down-regulation of about half of hexose transporters genes (four out of nine).

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia Serdang, Malaysia.

ABSTRACT
Candida glabrata is an emerging human fungal pathogen that has efficacious nutrient sensing and responsiveness ability. It can be seen through its ability to thrive in diverse range of nutrient limited-human anatomical sites. Therefore, nutrient sensing particularly glucose sensing is thought to be crucial in contributing to the development and fitness of the pathogen. This study aimed to elucidate the role of SNF3 (Sucrose Non Fermenting 3) as a glucose sensor and its possible role in contributing to the fitness and survivability of C. glabrata in glucose-limited environment. The SNF3 knockout strain was constructed and subjected to different glucose concentrations to evaluate its growth, biofilm formation, amphotericin B susceptibility, ex vivo survivability and effects on the transcriptional profiling of the sugar receptor repressor (SRR) pathway-related genes. The CgSNF3Δ strain showed a retarded growth in low glucose environments (0.01 and 0.1%) in both fermentation and respiration-preferred conditions but grew well in high glucose concentration environments (1 and 2%). It was also found to be more susceptible to amphotericin B in low glucose environment (0.1%) and macrophage engulfment but showed no difference in the biofilm formation capability. The deletion of SNF3 also resulted in the down-regulation of about half of hexose transporters genes (four out of nine). Overall, the deletion of SNF3 causes significant reduction in the ability of C. glabrata to sense limited surrounding glucose and consequently disrupts its competency to transport and perform the uptake of this critical nutrient. This study highlighted the role of SNF3 as a high affinity glucose sensor and its role in aiding the survivability of C. glabrata particularly in glucose limited environment.

No MeSH data available.


Related in: MedlinePlus

A model of glucose sensing in Candida glabrata under low glucose environment. The part of the pathway labeled with asteisks inferred from published works done on S. cerevisiae (Rolland et al., 2002; Santangelo, 2006; Gancedo, 2008). Hexose transporters are repressed by Std1-bounded-Rgt1 when there is no stimulation from glucose sensor located in the cell membrane. Presence of low concentration of glucose induced signal from high affinity glucose sensor, Snf3 to the phosphorylation of Std1 by the Yck kinase. Phosphorylated Std1 is then subjected to the SCFGrr1—mediated ubiquitination and degraded by proteasome. Degraded Std1 results in the activation of Rgt1, which then leads to derepression of downstream hexose transporters. Deletion of SNF3 gives rise to the disruption of hexose transporters expression and glucose uptake mechanism, therefore leads to the interference of Candida glabrata fitness under low glucose environment. However, the possible interaction between RGT2 and downstream HXT3/HXT5 (labeled with dotted line) is remains unclear and requires further investigation.
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Figure 9: A model of glucose sensing in Candida glabrata under low glucose environment. The part of the pathway labeled with asteisks inferred from published works done on S. cerevisiae (Rolland et al., 2002; Santangelo, 2006; Gancedo, 2008). Hexose transporters are repressed by Std1-bounded-Rgt1 when there is no stimulation from glucose sensor located in the cell membrane. Presence of low concentration of glucose induced signal from high affinity glucose sensor, Snf3 to the phosphorylation of Std1 by the Yck kinase. Phosphorylated Std1 is then subjected to the SCFGrr1—mediated ubiquitination and degraded by proteasome. Degraded Std1 results in the activation of Rgt1, which then leads to derepression of downstream hexose transporters. Deletion of SNF3 gives rise to the disruption of hexose transporters expression and glucose uptake mechanism, therefore leads to the interference of Candida glabrata fitness under low glucose environment. However, the possible interaction between RGT2 and downstream HXT3/HXT5 (labeled with dotted line) is remains unclear and requires further investigation.

Mentions: The transcriptional analysis on selected hexose transporters (HXTs) revealed that almost half (four out of nine) hexose transporters were down regulated with the removal of SNF3, together with the down-regulation of downstream casein kinase (YCK1 and YCK2) and STD1 (Figures 7, 8). The disruption of the signaling pathway for high affinity hexose transporters explained the compromised fitness of C. glabrata under low glucose environment (Figures 1–3) as this triggers the failure in transporting sufficient glucose to support its growth. In addition, data presented concurs with the view that the expression of transcription regulator, RGT1 is regulated by the glucose concentration but not affected by the signal generated from glucose sensors (Özcan and Johnston, 1999) as the expression of RGT1 remain unchanged even with the missing signal from SNF3. However, the direct regulation of glucose concentration on the expression level of RGT1 is still not fully understood. Nonetheless, the shutting down of these four hexose transporters did not diminish the growth of C. glabrata completely as there are two other hexose transporters that were still actively expressed namely the CAGL0A0232 (HXT3) and CAGL0A01826 (HXT5), together with the up regulation of RGT2. This could be a compensatory mechanism used by C. glabrata to compensate the loss of SNF3 with the activation of RGT2. Notably, these HXT3 and HXT5 were regarded as key hexose transporters for C. glabrata in low glucose environment from our previous work (Ng et al., 2015a). Nevertheless, this compensatory mechanism still failed to salvage C. glabrata from glucose uptake crisis as the growth defect is still significant (p-value < 0.05; Figures 1–3) in the absence of SNF3. We opine the compensation of glucose uptake by HXT3 and HXT5 is insufficient to provide the amount of glucose needed and this highlights the importance of four other repressed HXTs in supporting the growth of C. glabrata under low glucose environment. In addition, the capability of RGT2 to induce expression of HXT3 and HXT5 supports the view that SNF3 and RGT2 have separate but overlapping functions. Özcan et al. (1998) demonstrated the capability of SNF3 in S. cerevisiae to restore the expression of HXT1 (supposedly induce by RGT2) by 64%, in a RGT2 mutant. This observation suggests a complex and interconnected regulatory pathway of glucose sensing and uptake mechanism in yeast. From the data obtained, a model of glucose sensing in C. glabrata through the modulation of SNF3 is illustrated based on the understanding of the homolog and the inferred glucose sensing mechanism in S. cerevisiae (Figure 9). Further work is warranted, as the compensatory mechanism proposed here is still not fully deciphered. In addition, effort to study the transcriptional profile of the highly homologous HXTs genes using other approach should be carried out. With more complete information on the role of each hexose transporters present in C. glabrata, a clearer and more comprehensive picture on the role of SNF3 in SRR pathway will be achieved.


SNF3 as High Affinity Glucose Sensor and Its Function in Supporting the Viability of Candida glabrata under Glucose-Limited Environment.

Ng TS, Chew SY, Rangasamy P, Mohd Desa MN, Sandai D, Chong PP, Than LT - Front Microbiol (2015)

A model of glucose sensing in Candida glabrata under low glucose environment. The part of the pathway labeled with asteisks inferred from published works done on S. cerevisiae (Rolland et al., 2002; Santangelo, 2006; Gancedo, 2008). Hexose transporters are repressed by Std1-bounded-Rgt1 when there is no stimulation from glucose sensor located in the cell membrane. Presence of low concentration of glucose induced signal from high affinity glucose sensor, Snf3 to the phosphorylation of Std1 by the Yck kinase. Phosphorylated Std1 is then subjected to the SCFGrr1—mediated ubiquitination and degraded by proteasome. Degraded Std1 results in the activation of Rgt1, which then leads to derepression of downstream hexose transporters. Deletion of SNF3 gives rise to the disruption of hexose transporters expression and glucose uptake mechanism, therefore leads to the interference of Candida glabrata fitness under low glucose environment. However, the possible interaction between RGT2 and downstream HXT3/HXT5 (labeled with dotted line) is remains unclear and requires further investigation.
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Related In: Results  -  Collection

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Figure 9: A model of glucose sensing in Candida glabrata under low glucose environment. The part of the pathway labeled with asteisks inferred from published works done on S. cerevisiae (Rolland et al., 2002; Santangelo, 2006; Gancedo, 2008). Hexose transporters are repressed by Std1-bounded-Rgt1 when there is no stimulation from glucose sensor located in the cell membrane. Presence of low concentration of glucose induced signal from high affinity glucose sensor, Snf3 to the phosphorylation of Std1 by the Yck kinase. Phosphorylated Std1 is then subjected to the SCFGrr1—mediated ubiquitination and degraded by proteasome. Degraded Std1 results in the activation of Rgt1, which then leads to derepression of downstream hexose transporters. Deletion of SNF3 gives rise to the disruption of hexose transporters expression and glucose uptake mechanism, therefore leads to the interference of Candida glabrata fitness under low glucose environment. However, the possible interaction between RGT2 and downstream HXT3/HXT5 (labeled with dotted line) is remains unclear and requires further investigation.
Mentions: The transcriptional analysis on selected hexose transporters (HXTs) revealed that almost half (four out of nine) hexose transporters were down regulated with the removal of SNF3, together with the down-regulation of downstream casein kinase (YCK1 and YCK2) and STD1 (Figures 7, 8). The disruption of the signaling pathway for high affinity hexose transporters explained the compromised fitness of C. glabrata under low glucose environment (Figures 1–3) as this triggers the failure in transporting sufficient glucose to support its growth. In addition, data presented concurs with the view that the expression of transcription regulator, RGT1 is regulated by the glucose concentration but not affected by the signal generated from glucose sensors (Özcan and Johnston, 1999) as the expression of RGT1 remain unchanged even with the missing signal from SNF3. However, the direct regulation of glucose concentration on the expression level of RGT1 is still not fully understood. Nonetheless, the shutting down of these four hexose transporters did not diminish the growth of C. glabrata completely as there are two other hexose transporters that were still actively expressed namely the CAGL0A0232 (HXT3) and CAGL0A01826 (HXT5), together with the up regulation of RGT2. This could be a compensatory mechanism used by C. glabrata to compensate the loss of SNF3 with the activation of RGT2. Notably, these HXT3 and HXT5 were regarded as key hexose transporters for C. glabrata in low glucose environment from our previous work (Ng et al., 2015a). Nevertheless, this compensatory mechanism still failed to salvage C. glabrata from glucose uptake crisis as the growth defect is still significant (p-value < 0.05; Figures 1–3) in the absence of SNF3. We opine the compensation of glucose uptake by HXT3 and HXT5 is insufficient to provide the amount of glucose needed and this highlights the importance of four other repressed HXTs in supporting the growth of C. glabrata under low glucose environment. In addition, the capability of RGT2 to induce expression of HXT3 and HXT5 supports the view that SNF3 and RGT2 have separate but overlapping functions. Özcan et al. (1998) demonstrated the capability of SNF3 in S. cerevisiae to restore the expression of HXT1 (supposedly induce by RGT2) by 64%, in a RGT2 mutant. This observation suggests a complex and interconnected regulatory pathway of glucose sensing and uptake mechanism in yeast. From the data obtained, a model of glucose sensing in C. glabrata through the modulation of SNF3 is illustrated based on the understanding of the homolog and the inferred glucose sensing mechanism in S. cerevisiae (Figure 9). Further work is warranted, as the compensatory mechanism proposed here is still not fully deciphered. In addition, effort to study the transcriptional profile of the highly homologous HXTs genes using other approach should be carried out. With more complete information on the role of each hexose transporters present in C. glabrata, a clearer and more comprehensive picture on the role of SNF3 in SRR pathway will be achieved.

Bottom Line: Candida glabrata is an emerging human fungal pathogen that has efficacious nutrient sensing and responsiveness ability.It can be seen through its ability to thrive in diverse range of nutrient limited-human anatomical sites.The deletion of SNF3 also resulted in the down-regulation of about half of hexose transporters genes (four out of nine).

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia Serdang, Malaysia.

ABSTRACT
Candida glabrata is an emerging human fungal pathogen that has efficacious nutrient sensing and responsiveness ability. It can be seen through its ability to thrive in diverse range of nutrient limited-human anatomical sites. Therefore, nutrient sensing particularly glucose sensing is thought to be crucial in contributing to the development and fitness of the pathogen. This study aimed to elucidate the role of SNF3 (Sucrose Non Fermenting 3) as a glucose sensor and its possible role in contributing to the fitness and survivability of C. glabrata in glucose-limited environment. The SNF3 knockout strain was constructed and subjected to different glucose concentrations to evaluate its growth, biofilm formation, amphotericin B susceptibility, ex vivo survivability and effects on the transcriptional profiling of the sugar receptor repressor (SRR) pathway-related genes. The CgSNF3Δ strain showed a retarded growth in low glucose environments (0.01 and 0.1%) in both fermentation and respiration-preferred conditions but grew well in high glucose concentration environments (1 and 2%). It was also found to be more susceptible to amphotericin B in low glucose environment (0.1%) and macrophage engulfment but showed no difference in the biofilm formation capability. The deletion of SNF3 also resulted in the down-regulation of about half of hexose transporters genes (four out of nine). Overall, the deletion of SNF3 causes significant reduction in the ability of C. glabrata to sense limited surrounding glucose and consequently disrupts its competency to transport and perform the uptake of this critical nutrient. This study highlighted the role of SNF3 as a high affinity glucose sensor and its role in aiding the survivability of C. glabrata particularly in glucose limited environment.

No MeSH data available.


Related in: MedlinePlus