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RNA in development: how ribonucleoprotein granules regulate the life cycles of pathogenic protozoa

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Ribonucleoprotein (RNP) granules are important posttranscriptional regulators of messenger RNA (mRNA) fate. Several types of RNP granules specifically regulate gene expression during development of multicellular organisms and are commonly referred to as germ granules. The function of germ granules is not entirely understood and probably diverse, but it is generally agreed that one main function is posttranscriptional regulation of gene expression during early development, when transcription is silent. One example is the translational repression of maternally derived mRNAs in oocytes. Here, I hope to show that the need for regulation of gene expression by RNP granules is not restricted to animal development, but plays an equally important role during the development of pathogenic protozoa. Apicomplexa and Trypanosomatidae have complex life cycles with frequent host changes. The need to quickly adapt gene expression to a new environment as well as the ability to suppress translation to survive latencies is critical for successful completion of life cycles. Posttranscriptional gene regulation is not necessarily simpler in protozoa. Apicomplexa surprise with the presence of micro RNA (miRNAs) and upstream open reading frames (µORFs). Trypanosomes have an unusually large repertoire of different RNP granule types. A better understanding of RNP granules in protozoa may help to gain insight into the evolutionary origin of RNP granules: Trypanosomes for example have two types of granules with interesting similarities to animal germ granules. WIREs RNA 2014, 5:263–284. doi: 10.1002/wrna.1207 This article is categorized under: Translation > Translation Regulation RNA Export and Localization > RNA Localization RNA in Disease and Development > RNA in Development

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The Plasmodium life cycle and proteins identified in RNA granules. Plasmodium sporozoites are transmitted with the saliva of a female Anopheles mosquito to the mammalian host. Most parasites will enter the bloodstream and migrate to the liver to invade hepatocytes. Within the hepatocyte, the elongated sporozoites change to rounded forms and mature to huge schizonts within a parasitophorous vacuole. In some Plasmodium species, a dormant form called a hypnozoite precedes schizont maturation. Eventually, the parasitophorous vacuole ruptures and releases thousands of merozoites to the cytoplasm of the hepatocyte. As a consequence, the hepatocyte dies and detaches as hundreds or thousands of merozoites, organized into membrane‐bound sacs called merosomes, migrate to the lung. Within the small pulmonary capillaries of the lung tissue, merozoites are slowly released and infect erythrocytes, causing the typical clinical malaria symptoms. Within the erythrocytes, the parasites differentiate to a ring‐shaped form, followed by a larger trophozoite form and finally by the schizont form, that divides and releases new merozoites into the blood that can invade new red blood cells. Some merozoites will differentiate into male or female gametocytes within the erythrocyte. Five different gametocyte stages can be distinguished by morphology. Gametocytes are transmitted back to the Anopheles midgut, where they develop into gametes. Male and female gametes fuse to a diploid zygote that undergoes meiosis and differentiates into the truly infective form, the motile, invasive ookinete. This process takes 18 h. The ookinetes continue their way through the mosquito and finally attach to the exterior of the gut membrane where they differentiate into oocysts. Each oocyst produces hundreds of tiny elongated sporozoites that are eventually released by oocyst rupture and migrate to the salivary gland of the mosquito. The highly infective sporozoites are transmitted to the mammalian host with the next blood meal of the mosquito. Sporozoites can remain in the salivary gland for many days without losing infectivity. Proteins and RNA that have been described in RNA granules are indicated in yellow boxes; references are in the text.
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Trypanosomatidae. (a–c) Simplified schematics of the Trypanosoma brucei, Trypanosoma cruzi, and Leishmania life cycles. The non‐proliferative life‐cycle stages are shown in red. (d) RNP granules of Trypanosomatidae. Fluorescence microscopy images of the different types of trypanosome RNP granules from T. cruzi (tRNA half‐granules, image kindly provided by Maria Rosa Garcia‐Silva and Alfonso Cayoto, Montevideo, Uruguay) and T. brucei (all others) are shown. Proteins/RNA that were unequivocally identified in the granules in at least one of the Tritryps are indicated below the images. Arrows point to the specific granules. TcPUF6 does colocalize with TcDHH1 to foci in the proliferative epimastigote life‐cycle stage only. TbPABP1 is found in nutrient starvation stress granules only when overexpressed. All references for the localization to granules are indicated for each protein. More details are in the text.
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The Toxoplasma life cycle. A cat, the definite feline host of Toxoplasma, usually gets infected when consuming an infected animal, such as a bird or rat. During passage through the cat stomach and intestine, the slowly dividing bradyzoite forms of Toxoplasma are released from the tissue cysts of the prey animal and eventually invade epithelial cells of the cat small intestine. Within epithelial cells, bradyzoites differentiate to either the fast dividing asexual tachyzoite form or to male and female gametocytes. The latter fuse to a zygote and produce millions of oocysts. Eventually, the intestinal cells rupture and the highly resilient, thick‐walled oocysts are excreted with the cat feces; they are stable for years. Oocysts are then transmitted to the next host, usually to an intermediate host, such as a human who eats vegetables contaminated with cat feces. The cyst wall is resolved in the stomach and small intestine of the intermediate host, releasing the infectious sporozoites from the oocysts. Sporozoites will invade epithelial cells and differentiate into the highly motile, fast‐replicating, tachyzoite form that is responsible for the acute phase of toxoplasmosis. Replication takes place inside a parasitophorous vacuole, until the cell bursts and tachyzoites are released into the extracellular environment (egress). Extracellular tachyzoites can invade new cells and are spread to distant places with the bloodstream. The acute phase of toxoplasmosis is quickly followed by a chronic phase: tachyzoites differentiate into the slowly dividing bradyzoites, which form cysts within host cells (tissue cysts). Such tissue cysts are then transferred back to the definite host, finishing the life cycle. The two stages that are most important in the context of translational repression and ribonucleoprotein (RNP) granules, the bradyzoites and the extracellular tachyzoites, are marked in red. RNP granules were described in extracellular bradyzoites and tachyzoites, but are absent from the intracellular stages. The granules contain messenger RNAs (mRNAs) as well as poly (A) binding protein (yellow boxes).
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Translation > Translation Regulation
RNA in Disease and Development > RNA in Development
RNA Export and Localization > RNA Localization

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