Histoplasma capsulatum requires peroxisomes for multiple virulence functions including siderophore biosynthesis.
Histoplasma capsulatum requires peroxisomes for multiple virulence functions including siderophore biosynthesis.
复制标题
作者：
过氧化物体是真核生物中具有多种功能的细胞器，在真菌中具有多种功能，包括脂肪酸代谢、活性氧解毒和次生代谢物的生物合成。一组PEX蛋白(过氧化物素)维持着过氧酶体，而过氧酶体基质酶则执行过氧酶体的功能。插入诱变发现，过氧化物素基因是支持真菌病原体组织胞浆在吞噬体内生长的基本成分。破坏包膜螺旋藻中的Pex5、Pex10或Pex33过氧化物酶可以阻止通过PTS1途径靶向细胞器的蛋白质的过氧化物酶体输入。在急性组织胞浆菌感染模型中，这种过氧酶体蛋白输入的丢失限制了巨噬细胞内的包膜螺旋体的细胞内生长，并减弱了毒力。阻断替代的pts2输入途径也能减弱被囊藻的毒力，尽管只是在感染后的时间点。Sid1和Sid3铁载体生物合成蛋白含有PTS1过氧酶体输入信号，并定位于囊藻过氧酶体。PTS1或PTS2过氧体输入途径的缺失损害了囊藻中铁载体的产生和铁的获取，表明羟甲酸铁载体生物合成的至少一些生物合成步骤是区隔的。然而，与失去基于pts2的蛋白输入或铁载体生物合成相比，失去基于PTS1的过氧化体导入导致毒力下降的时间更早，这表明额外的依赖于PTS1的过氧化体功能对囊状血吸虫的毒力是重要的。此外，破坏Pex11过氧化物素还可以独立于过氧化物体蛋白的输入和铁载体的生物合成来减弱荚膜螺旋体的毒力。这些发现表明，过氧化物体通过促进铁载体的生物合成和细胞器在真菌毒力中的另一个未确定的角色(S)参与了包膜梭菌的致病过程。真菌病原体组织胞浆菌感染宿主吞噬细胞，并在细胞内建立允许复制的生态位。为了做到这一点，胶囊H.克服并颠覆了包括必需微量营养素限制在内的抗真菌防御机制。在宿主细胞内复制囊状杆菌需要真菌过氧化物体细胞器的多种不同功能。这些过氧化体功能在感染过程中的不同时间参与了包膜螺旋体的致病过程，包括依赖于过氧化酶体的铁清除铁载体的生物合成，以促进真菌的增殖，特别是在激活细胞免疫之后。真菌过氧化酶体的多种重要作用揭示了这种细胞器作为潜在的但尚未开发的治疗药物开发的靶点。
Peroxisomes are versatile eukaryotic organelles essential for many functions in fungi, including fatty acid metabolism, reactive oxygen species detoxification, and secondary metabolite biosynthesis. A suite of Pex proteins (peroxins) maintains peroxisomes, while peroxisomal matrix enzymes execute peroxisome functions. Insertional mutagenesis identified peroxin genes as essential components supporting the intraphagosomal growth of the fungal pathogen Histoplasma capsulatum. Disruption of the peroxins Pex5, Pex10, or Pex33 in H. capsulatum prevented peroxisome import of proteins targeted to the organelle via the PTS1 pathway. This loss of peroxisome protein import limited H. capsulatum intracellular growth in macrophages and attenuated virulence in an acute histoplasmosis infection model. Interruption of the alternate PTS2 import pathway also attenuated H. capsulatum virulence, although only at later time points of infection. The Sid1 and Sid3 siderophore biosynthesis proteins contain a PTS1 peroxisome import signal and localize to the H. capsulatum peroxisome. Loss of either the PTS1 or PTS2 peroxisome import pathway impaired siderophore production and iron acquisition in H. capsulatum, demonstrating compartmentalization of at least some biosynthetic steps for hydroxamate siderophore biosynthesis. However, the loss of PTS1-based peroxisome import caused earlier virulence attenuation than either the loss of PTS2-based protein import or the loss of siderophore biosynthesis, indicating additional PTS1-dependent peroxisomal functions are important for H. capsulatum virulence. Furthermore, disruption of the Pex11 peroxin also attenuated H. capsulatum virulence independently of peroxisomal protein import and siderophore biosynthesis. These findings demonstrate peroxisomes contribute to H. capsulatum pathogenesis by facilitating siderophore biosynthesis and another unidentified role(s) for the organelle during fungal virulence. The fungal pathogen Histoplasma capsulatum infects host phagocytes and establishes a replication-permissive niche within the cells. To do so, H. capsulatum overcomes and subverts antifungal defense mechanisms which include the limitation of essential micronutrients. H. capsulatum replication within host cells requires multiple distinct functions of the fungal peroxisome organelle. These peroxisomal functions contribute to H. capsulatum pathogenesis at different times during infection and include peroxisome-dependent biosynthesis of iron-scavenging siderophores to enable fungal proliferation, particularly after activation of cell-mediated immunity. The multiple essential roles of fungal peroxisomes reveal this organelle as a potential but untapped target for the development of therapeutics.
登录
查看更多内容
影响因子：
3.5
作者：
Habich, C;Kempe, K;Burkart, V
通讯作者：
Burkart, V
影响因子：
3.6
作者：
Gründlinger M;Yasmin S;Lechner BE;Geley S;Schrettl M;Hynes M;Haas H
通讯作者：
Haas H
DOI：
10.1111/febs.13389
发表时间：
2016-02
期刊：
The FEBS journal
影响因子：
--
作者：
Garfoot AL;Rappleye CA
通讯作者：
Rappleye CA
影响因子：
11.9
作者：
Haas H
通讯作者：
Haas H
影响因子：
3.9
作者：
ANDERSON, GJ;LESUISSE, E;KLAUSNER, RD
通讯作者：
KLAUSNER, RD