Leishmania major telomerase RNA knockout: From altered cell proliferation to decreased parasite infectivity

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Oliveira, Beatriz Cristina Dias de ; Shiburah, Mark Ewusi ; Assis, Luiz Henrique Castro ; Fontes, Veronica Silva ; Bisetegn, Habtye ; Passos, Arthur de Oliveira ; de Oliveira, Leilane S. ; Alves, Cristiane de Santis ; Ernst, Evan ; Martienssen, Rob ; Gallo-Francisco, Pedro Henrique ; Giorgio, Selma ; Batista, Marcos Meuser ; Soeiro, Maria de Nazare Correia ; Menna-Barreto, Rubem Figueiredo Sadok ; Aoki, Juliana Ide ; Coelho, Adriano Cappellazzo ; Cano, Maria Isabel Nogueira

• Document type: Journal article
• Source: International Journal of Biological Macromolecules; v. 279, p. 20-pg., 2024-09-06.

Abstract

This study focuses on the biological impacts of deleting the telomerase RNA from Leishmania major (LeishTER), a parasite responsible for causing leishmaniases, for which no effective treatment or prevention is available. TER is a critical player in the telomerase ribonucleoprotein complex, containing the template sequence copied by the reverse transcriptase component during telomere elongation. The success of knocking out both LeishTER alleles was confirmed, and no off-targets were detected. LmTER- /- cells share similar characteristics with other TERdepleted eukaryotes, such as altered growth patterns and partial G0/G1 cell cycle arrest in early passages, telomere shortening, and elevated TERRA expression. They also exhibit increased gamma H2A phosphorylation, suggesting that the loss of LeishTER induces DNA damage signaling. Moreover, pro-survival autophagic signals and mitochondrion alterations were shown without any detectable plasma membrane modifications. LmTER- /retained the ability to transform into metacyclics, but their infectivity capacity was compromised. Furthermore, the overexpression of LeishTER was also deleterious, inducing a dominant negative effect that led to telomere shortening and growth impairments. These findings highlight TER's vital role in parasite homeostasis, opening discussions about its potential as a drug target candidate against Leishmania. (AU)

• FAPESP's process: 18/04375-2 - Studies about the biogenesis and composition of the Leishmania spp. ribonucleoprotein complex and its regulation
• Grantee: Maria Isabel Nogueira Cano
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 20/00316-1 - Studies about the function of L. major TERT component in telomere maintenance and cell proliferation
• Grantee: Mark Ewusi Shiburah
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 19/11061-7 - Effect of the interaction of macrophages co-cultivated with Leishmania spp. and bacteria in the control of parasitic infection
• Grantee: Pedro Henrique Gallo Francisco
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 21/04253-7 - Role of TERRA in telomere regulation and replicative senescence in Leishmania major
• Grantee: Luiz Henrique de Castro Assis
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/25985-6 - Studies about the effect of knocking out and overexpressing the Telomerase RNA component in L. major development and survival
• Grantee: Beatriz Cristina Dias de Oliveira
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 16/21171-6 - Paromomycin for the treatment of Tegumentary Leishmaniasis: investigation in vitro, in vivo and in the identification of molecular markers associated with susceptibility and resistance
• Grantee: Adriano Cappellazzo Coelho
• Support Opportunities: Research Grants - Young Investigators Grants