Deoxyhypusine Modification of Eukaryotic Translation Initiation Factor 5A (eIF5A) Is Essential for Trypanosoma brucei Growth and for Expression of Polyprolyl-containing Proteins

Nguyen, Suong; Leija, Chrisopher; Kinch, Lisa N.; Regmi, Sandesh; Li, Qiong; Grishin, Nick V.; Phillips, Margaret A.

doi:10.1074/jbc.m115.656785

Cited by 24 publications

(18 citation statements)

References 50 publications

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“…Nevertheless, the degree of activation observed in trypanosome enzyme-prozyme pairs is exceptional. It has been postulated that the dramatic control of enzyme activities via the enzyme-prozyme mechanism was expanded in trypanosomes in response to their lack of transcriptional control and the almost exclusive reliance on posttranscriptional and posttranslational mechanisms of gene regulation (43). The present study is the first report of an enzymeprozyme complex in trypanosomes outside the polyamine synthesis pathway.…”

Section: Discussionmentioning

confidence: 63%

The Major Protein Arginine Methyltransferase in Trypanosoma brucei Functions as an Enzyme-Prozyme Complex

Kafková

Debler

Fisk

et al. 2017

Journal of Biological Chemistry

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Edited by John M. DenuProzymes are catalytically inactive enzyme paralogs that dramatically stimulate the function of weakly active enzymes through complex formation. The two prozymes described to date reside in the polyamine biosynthesis pathway of the human parasite Trypanosoma brucei, an early branching eukaryote that lacks transcriptional regulation and regulates its proteome through posttranscriptional and posttranslational means. Arginine methylation is a common posttranslational modification in eukaryotes catalyzed by protein arginine methyltransferases (PRMTs) that are typically thought to function as homodimers. We demonstrate that a major T. brucei PRMT, TbPRMT1, functions as a heterotetrameric enzyme-prozyme pair. The inactive PRMT paralog, TbPRMT1 PRO , is essential for catalytic activity of the TbPRMT1 ENZ subunit. Mutational analysis definitively demonstrates that TbPRMT1 ENZ is the cofactor-binding subunit and carries all catalytic activity of the complex. Our results are the first demonstration of an obligate heteromeric PRMT, and they suggest that enzyme-prozyme organization is expanded in trypanosomes as a posttranslational means of enzyme regulation.

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Section: Discussionmentioning

confidence: 63%

The Major Protein Arginine Methyltransferase in Trypanosoma brucei Functions as an Enzyme-Prozyme Complex

Kafková

Debler

Fisk

et al. 2017

Journal of Biological Chemistry

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“…Gutierrez et al (85) also reported evidence that eIF5A similarly stimulates peptide bond formation at consecutive proline sequences in S. cerevisiae. Additional evidence for the importance of eIF5A in translation of polyproline proteins was reported in T. brucei (86). Recent ribosome profile data demonstrate that eIF5A works more generally at many ribosome-stalled sites and that it also enhances translation termination (87,88).…”

Section: Mode Of Action Of Eif5a In Translationmentioning

confidence: 82%

Hypusine, a polyamine-derived amino acid critical for eukaryotic translation

Park

Wolff

2018

Journal of Biological Chemistry

159

122

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“…For example, hypusinated eIF5a modulates mitochondrial respiration and macrophage activation via promoting the efficient expression of a subset of mitochondrial proteins involved in the tricarboxylic acid cycle and oxidative phosphorylation (Puleston et al, 2019). eIF5a is also required for efficient translation of mRNAs encoding proteins with poly(Pro) tracts (such as PPP or PPG) by preventing ribosomes from stalling at such sequences (Pereira et al, 2016;Nguyen et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

eIF5a reduction via decreased Klf5 leads to cell senescence by mitochondrial fission in VSMCs

Zheng

et al. 2019

Preprint

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Though dysregulation of mitochondrial dynamics has been linked to cellular senescence, which contributes to advanced age-related disorders, it is unclear how Klf5, an essential transcriptional factor of cardiovascular remodeling, mediates the link between mitochondrial dynamics and vascular smooth muscle cell (VSMC) senescence. Here we show that Klf5 downregulation in VSMCs is correlated with rupture of abdominal aortic aneurysm (AAA), an age-related vascular disease. Mice lacking Klf5 in VSMCs exacerbate vascular senescence and progression of Ang II-induced AAA by facilitating ROS formation. Klf5 knockdown enhances, while Klf5 overexpression suppresses mitochondrial fission. Mechanistically, Klf5 activates eIF5a transcription through binding to the promoter of eIF5a, which in turn preserves mitochondrial integrity by interacting with Mfn1. Accordingly, decreased expression of eIF5a elicited by Klf5 downregulation leads to mitochondrial fission and excessive ROS production. Inhibition of mitochondrial fission decreases ROS production and VSMC senescence. Our studies provide a potential therapeutic target for age-related vascular disorders.

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Deoxyhypusine Modification of Eukaryotic Translation Initiation Factor 5A (eIF5A) Is Essential for Trypanosoma brucei Growth and for Expression of Polyprolyl-containing Proteins

Cited by 24 publications

References 50 publications

The Major Protein Arginine Methyltransferase in Trypanosoma brucei Functions as an Enzyme-Prozyme Complex

The Major Protein Arginine Methyltransferase in Trypanosoma brucei Functions as an Enzyme-Prozyme Complex

Hypusine, a polyamine-derived amino acid critical for eukaryotic translation

eIF5a reduction via decreased Klf5 leads to cell senescence by mitochondrial fission in VSMCs

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