New Insights into the Molecular Mechanisms of Mitosis and Cytokinesis in Trypanosomes

Zhou, Qing; Hu, Huiqing; Li, Ziyin

doi:10.1016/b978-0-12-800097-7.00004-x

Cited by 28 publications

(26 citation statements)

References 139 publications

(238 reference statements)

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“…Trypanosomatids follow a closed type of mitosis where the nuclear envelope does not disrupt during the mitosis (Ogbadoyi et al ., ; Zhou et al ., ) and unlike higher eukaryotes (Hernandez‐Verdun, ), their nucleoli also remain intact throughout the cell division cycle (Boucher et al ., ). To have an insight into the role of nucleolar TWF during cell division, we examined the dividing Leishmania cells using confocal microscopy after their labelling with anti TWF and anti α‐tubulin antibodies.…”

Section: Resultsmentioning

confidence: 99%

A twinfilin‐like protein coordinates karyokinesis by influencing mitotic spindle elongation and DNA replication in Leishmania

Kumar

Kajuluri

Gupta

et al. 2016

Molecular Microbiology

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Twinfilin is an evolutionarily conserved actin-binding protein, which regulates actin-dynamics in eukaryotic cells. Homologs of this protein have been detected in the genome of various protozoan parasites causing diseases in human. However, very little is known about their core functions in these organisms. We show here that a twinfilin homolog in a human pathogen Leishmania, primarily localizes to the nucleolus and, to some extent, also in the basal body region. In the dividing cells, nucleolar twinfilin redistributes to the mitotic spindle and remains there partly associated with the spindle microtubules. We further show that approximately 50% depletion of this protein significantly retards the cell growth due to sluggish progression of S phase of the cell division cycle, owing to the delayed nuclear DNA synthesis. Interestingly, overexpression of this protein results in significantly increased length of the mitotic spindle in the dividing Leishmania cells, whereas, its depletion adversely affects spindle elongation and architecture. Our results indicate that twinfilin controls on one hand, the DNA synthesis and on the other, the mitotic spindle elongation, thus contributing to karyokinesis in Leishmania.

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Section: Resultsmentioning

confidence: 99%

A twinfilin‐like protein coordinates karyokinesis by influencing mitotic spindle elongation and DNA replication in Leishmania

Kumar

Kajuluri

Gupta

et al. 2016

Molecular Microbiology

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“…In the early branching parasitic protozoan Trypanosoma brucei, 11 CDK-related kinases, designated CRK1-CRK4 and CRK6 -CRK12, have been identified (22,23). CRK1 and CRK3 are involved in controlling the G 1 /S transition and the G 2 /M transition, respectively (24 -26).…”

mentioning

confidence: 99%

The G1 Cyclin-dependent Kinase CRK1 in Trypanosoma brucei Regulates Anterograde Protein Transport by Phosphorylating the COPII Subunit Sec31

Gourguechon

Wang

et al. 2016

Journal of Biological Chemistry

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Transport of secretory proteins from the endoplasmic reticulum to the Golgi is mediated by the coat protein II (COPII) complex comprising a Sec23-Sec24 heterodimer and a Sec13-Sec31 heterotetramer. The mechanisms underlying COPII-mediated protein trafficking have been well defined, but the extent of regulation of this secretory machinery by cellular signaling pathways remains poorly understood. Here, we report that CRK1, a G 1 cyclin-dependent kinase in Trypanosoma brucei, regulates anterograde protein trafficking by phosphorylating Sec31. Depletion of CRK1 abolished anterograde transport of the secretory protein and disrupted the localization of multiple Golgi proteins, reminiscent of Sec31 depletion. CRK1 phosphorylates Sec31 at multiple serine/threonine sites, and mutation of these phosphosites to alanine recapitulates the protein trafficking defects caused by Sec31 depletion. Mutation of these CRK1 phosphosites to aspartate restored Sec31 function. Taken together, these results uncover a novel function of CRK1 in anterograde protein trafficking and elucidate the mechanistic role of CRK1 in protein trafficking through regulation of the COPII subunit Sec31.

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“…2) indicated that the drug blocked the entry of trypanosomes into the S-phase. The bilobe, a centrincontaining cytoskeletal structure at the base of the flagellum (Esson et al, 2012), is duplicated in S-phase (Zhou et al, 2014). We postulated that because AEE788 prevented S-phase entry (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Division of the kinetoplast precedes mitosis forming a 2K1N population (Woodward and Gull, 1990). Mitosis produces 2K2N trypanosomes, which become two 1K1N cells after cytokinesis (Sherwin and Gull, 1989), completing the division cycle (for review, see Hammarton, 2007;Li, 2012;Zhou et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

AEE788 Inhibits Basal Body Assembly and Blocks DNA Replication in the African Trypanosome

et al. 2017

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causes human African trypanosomiasis (HAT). The pyrrolopyrimidine AEE788 (a hit for anti-HAT drug discovery) associates with three trypanosome protein kinases. Herein we delineate the effects of AEE788 on using chemical biology strategies. AEE788 treatment inhibits DNA replication in the kinetoplast (mitochondrial nucleoid) and nucleus. In addition, AEE788 blocks duplication of the basal body and the bilobe without affecting mitosis. Thus, AEE788 prevents entry into the S-phase of the cell division cycle. To study the kinetics of early events in trypanosome division, we employed an "AEE788 block and release" protocol to stage entry into the S-phase. A time-course of DNA synthesis (nuclear and kinetoplast DNA), duplication of organelles (basal body, bilobe, kinetoplast, nucleus), and cytokinesis was obtained. Unexpected findings include the following: 1) basal body and bilobe duplication are concurrent; 2) maturation of probasal bodies, marked by TbRP2 recruitment, is coupled with nascent basal body assembly, monitored by localization of TbSAS6 at newly forming basal bodies; and 3) kinetoplast division is observed in G2 after completion of nuclear DNA synthesis. Prolonged exposure of trypanosomes to AEE788 inhibited transferrin endocytosis, altered cell morphology, and decreased cell viability. To discover putative effectors for the pleiotropic effects of AEE788, proteome-wide changes in protein phosphorylation induced by the drug were determined. Putative effectors include an SR protein kinase, bilobe proteins, TbSAS4, TbRP2, and BILBO-1. Loss of function of one or more of these effectors can, from published literature, explain the polypharmacology of AEE788 on trypanosome biology.

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New Insights into the Molecular Mechanisms of Mitosis and Cytokinesis in Trypanosomes

Cited by 28 publications

References 139 publications

A twinfilin‐like protein coordinates karyokinesis by influencing mitotic spindle elongation and DNA replication in Leishmania

A twinfilin‐like protein coordinates karyokinesis by influencing mitotic spindle elongation and DNA replication in Leishmania

The G1 Cyclin-dependent Kinase CRK1 in Trypanosoma brucei Regulates Anterograde Protein Transport by Phosphorylating the COPII Subunit Sec31

AEE788 Inhibits Basal Body Assembly and Blocks DNA Replication in the African Trypanosome

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