Trypanosoma brucei TIF2 suppresses VSG switching by maintaining subtelomere integrity

Jehi, Sanaa E.; Wu, Fan; Li, Bibo

doi:10.1038/cr.2014.60

Cited by 54 publications

(126 citation statements)

References 69 publications

Supporting

Mentioning

122

Contrasting

Order By: Relevance

“…From an evolutionary perspective, there is a striking similarity between (i) our finding that the genes encoding glycocalyx components involved in immunosuppression in cancer cells are regulated by TRF2 and (ii) the antigenic variation employed by various pathogens to bypass the host immune response, involving the regulation of genes encoding plasma membrane proteins by TRF2 homologs (Jehi et al, 2014). This similarity suggests a conserved mechanism that couple telomere status to cell-surface composition, which is likely to ensure efficient coordination between telomere changes and the interaction of cells with their environment.…”

Section: Discussionmentioning

confidence: 97%

Cancer cells induce immune escape via glycocalyx changes controlled by the telomeric protein TRF 2

et al. 2019

View full text Add to dashboard Cite

Myeloid‐derived suppressor cells (MDSCs) are immature myeloid cells with strong immunosuppressive activity that promote tumor growth. In this study, we describe a mechanism by which cancer cells control MDSCs in human cancers by upregulating TRF2, a protein required for telomere stability. Specifically, we showed that the TRF2 upregulation in cancer cells has extratelomeric roles in activating the expression of a network of genes involved in the biosynthesis of heparan sulfate proteoglycan, leading to profound changes in glycocalyx length and stiffness, as revealed by atomic force microscopy. This TRF2‐dependent regulation facilitated the recruitment of MDSCs, their activation via the TLR2/MyD88/IL‐6/STAT3 pathway leading to the inhibition of natural killer recruitment and cytotoxicity, and ultimately tumor progression and metastasis. The clinical relevance of these findings is supported by our analysis of cancer cohorts, which showed a correlation between high TRF2 expression and MDSC infiltration, which was inversely correlated with overall patient survival.

show abstract

Section: Discussionmentioning

confidence: 97%

Cancer cells induce immune escape via glycocalyx changes controlled by the telomeric protein TRF 2

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Active transcription is known to favor homologous recombination (37). RNAi knockdown of the telomeric proteins TbTRF or TbTRF-interacting factor 2 (TbTIF2) increased VSG switching rates in T. brucei BF (38,39). The loss of these proteins appears to have enhanced repair and recombination.…”

Section: Discussionmentioning

confidence: 99%

Inositol phosphate pathway controls transcription of telomeric expression sites in trypanosomes

Cestari

Stuart

2015

Proc. Natl. Acad. Sci. U.S.A.

143

View full text Add to dashboard Cite

African trypanosomes evade clearance by host antibodies by periodically changing their variant surface glycoprotein (VSG) coat. They transcribe only one VSG gene at a time from 1 of about 20 telomeric expression sites (ESs). They undergo antigenic variation by switching transcription between telomeric ESs or by recombination of the VSG gene expressed. We show that the inositol phosphate (IP) pathway controls transcription of telomeric ESs and VSG antigenic switching in Trypanosoma brucei. Conditional knockdown of phosphatidylinositol 5-kinase (TbPIP5K) or phosphatidylinositol 5-phosphatase (TbPIP5-Pase) or overexpression of phospholipase C (TbPLC) derepresses numerous silent ESs in T. brucei bloodstream forms. The derepression is specific to telomeric ESs, and it coincides with an increase in the number of colocalizing telomeric and RNA polymerase I foci in the nucleus. Monoallelic VSG transcription resumes after reexpression of TbPIP5K; however, most of the resultant cells switched the VSG gene expressed. TbPIP5K, TbPLC, their substrates, and products localize to the plasma membrane, whereas TbPIP5Pase localizes to the nucleus proximal to telomeres. TbPIP5Pase associates with repressor/activator protein 1 (TbRAP1), and their telomeric silencing function is altered by TbPIP5K knockdown. These results show that specific steps in the IP pathway control ES transcription and antigenic switching in T. brucei by epigenetic regulation of telomere silencing.O nly one of the ∼20 telomeric expression sites (ESs) is transcribed at a time in Trypanosoma brucei in the mammalian infectious stage bloodstream (BF) or metacyclic forms (MFs), whereas no ES is transcribed in the insect stage procyclic forms (PFs) (1). Each ES contains 1 telomeric variant surface glycoprotein (VSG) gene, whose expression confers a distinct cellular antigenic type and up to 12 expression site-associated genes (ESAGs) whose functions are incompletely understood ( Fig. 1A) (2-4). The parasites evade immune clearance by periodically changing antigenic type by switching transcription between ESs or by ES recombination with the ∼2,500 non-ES VSG genes and pseudogenes (5, 6). ESs are transcribed by RNA polymerase I (Pol I), which initiates at the single promoter at all ESs but terminates within a few kilobases except at one fully transcribed ES (7,8).RNAi knockdown of expression of the nuclear protein TbRAP1 that interacts with the TTAGGG-binding factor (TbTRF) or of the nuclear lamina protein 1 (TbNUP1) or deletion of the histonelysine N-methyltransferase DOT1B (TbDOT1B) alleles each results in transcription of silent ESs (9-11). Similarly, RNAi knockdown of the transcription facilitating histone chaperone suppressor of ty 16 (TbSPT16) or the SWI2/SNF2-related chromatin-remodeling protein TbISWI or deletion of histone deacetylase sirtuin 2-related protein 1 (TbSIR2RP1) each increases transcription near the promoter but not the VSG gene of silent . These results indicate that the control of ES transcription involves telomeric silencing (15), which entails...

show abstract

“…Recently, we showed that telomere proteins are also important for maintaining subtelomere integrity and stability (24,25,27). In addition, telomeres suppress expression of nearby genes by telomeric silencing (28).…”

Section: Introductionmentioning

confidence: 99%

Trypanosoma brucei RAP1 maintains telomere and subtelomere integrity by suppressing TERRA and telomeric RNA:DNA hybrids

Nanavaty

Sandhu

Jehi

et al. 2017

Nucleic Acids Research

Self Cite

121

View full text Add to dashboard Cite

Trypanosoma brucei causes human African trypanosomiasis and regularly switches its major surface antigen, VSG, thereby evading the host's immune response. VSGs are monoallelically expressed from subtelomeric expression sites (ESs), and VSG switching exploits subtelomere plasticity. However, subtelomere integrity is essential for T. brucei viability. The telomeric transcript, TERRA, was detected in T. brucei previously. We now show that the active ES-adjacent telomere is transcribed. We find that TbRAP1, a telomere protein essential for VSG silencing, suppresses VSG gene conversion-mediated switching. Importantly, TbRAP1 depletion increases the TERRA level, which appears to result from longer read-through into the telomere downstream of the active ES. Depletion of TbRAP1 also results in more telomeric RNA:DNA hybrids and more double strand breaks (DSBs) at telomeres and subtelomeres. In TbRAP1-depleted cells, expression of excessive TbRNaseH1, which cleaves the RNA strand of the RNA:DNA hybrid, brought telomeric RNA:DNA hybrids, telomeric/subtelomeric DSBs and VSG switching frequency back to WT levels. Therefore, TbRAP1-regulated appropriate levels of TERRA and telomeric RNA:DNA hybrid are fundamental to subtelomere/telomere integrity. Our study revealed for the first time an important role of a long, non-coding RNA in antigenic variation and demonstrated a link between telomeric silencing and subtelomere/telomere integrity through TbRAP1-regulated telomere transcription.

show abstract

Trypanosoma brucei TIF2 suppresses VSG switching by maintaining subtelomere integrity

Cited by 54 publications

References 69 publications

Cancer cells induce immune escape via glycocalyx changes controlled by the telomeric protein TRF 2

Cancer cells induce immune escape via glycocalyx changes controlled by the telomeric protein TRF 2

Inositol phosphate pathway controls transcription of telomeric expression sites in trypanosomes

Trypanosoma brucei RAP1 maintains telomere and subtelomere integrity by suppressing TERRA and telomeric RNA:DNA hybrids

Contact Info

Product

Resources

About