Rab5b function is essential to acquire heme from hemoglobin endocytosis for survival of Leishmania

Rastogi, Ruchir; Kapoor, Anjali; Verma, Jaya; Ansari, Irshad; Sood, Chandni; Kumar, Kamal; Mukhopadhyay, Asok

doi:10.1016/j.bbamcr.2020.118868

Cited by 7 publications

(6 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, we demonstrated that intracellular amastigotes also express Hb receptor and mediates Hb endocytosis through this receptor to acquire heme from the degradation of internalized Hb for their intracellular survival [21]. Therefore, we checked whether HbR 41-80 peptide inhibits Hb uptake in amastigotes.…”

Section: Resultsmentioning

confidence: 99%

Identification and characterization of the hemoglobin‐binding domain of hemoglobin receptor in Leishmania

Rastogi

Verma²,

Singh

et al. 2021

FEBS Letters

Self Cite

View full text Add to dashboard Cite

Leishmania internalize hemoglobin (Hb) via a specific receptor (HbR) for their survival. To identify the Hb-binding domain of HbR, we cloned and expressed several truncated proteins of HbR and determined their ability to bind Hb. Our findings reveal that 90% of Hb-binding activity is retained in HbR 41-80 in comparison with HbR 1-471. We synthesized a 40 amino acid peptide (SSEKMKQLTMYMIHEMVEGLEGRPSTVRMLPSFVYTSDPA) corresponding to HbR 41-80 and found that it specifically binds Hb. Subsequently, we found that the HbR 41-80 peptide completely blocks Hb uptake in both promastigote and amastigote forms of Leishmania and, thereby, inhibits the growth of the parasite. These results demonstrate that HbR 41-80 is the Hb-binding domain of HbR, which might be used as a potential therapeutic agent to inhibit the growth of Leishmania.

show abstract

Section: Resultsmentioning

confidence: 99%

Identification and characterization of the hemoglobin‐binding domain of hemoglobin receptor in Leishmania

Rastogi

Verma²,

Singh

et al. 2021

FEBS Letters

Self Cite

View full text Add to dashboard Cite

show abstract

“…Leishmania amastigotes express a high-affinity hemoglobin receptor (HbR), located in the flagellar pocket. Then, different Rab GTPases/SNARE proteins mediate its internalization to the lysosome, where hemoglobin is degraded, and the heme group is released and transported to its final intracellular destination [31,32]. Therefore, it has been proposed that hemoglobin trafficking pathways could be an unexploited approach for new therapeutic strategies.…”

Section: How Do Amps and Cpps Specifically Target Protozoan Parasites...mentioning

confidence: 99%

Neglected Zoonotic Diseases: Advances in the Development of Cell-Penetrating and Antimicrobial Peptides against Leishmaniosis and Chagas

Robledo,

Pérez-Silanes,

Fernández-Rubio

et al. 2023

Preprint

View full text Add to dashboard Cite

In 2020, the WHO established a road map for neglected tropical diseases 2021−2030 that aims to control and eradicate 20 diseases, including Leishmaniosis and Chagas disease. In addition, since 2015, the WHO has been developing a Global Action Plan on Antimicrobial Resistance. In this context, the achievement of innovative strategies as an alternative to replace conventional therapies is a first-order socio-sanitary priority, especially regarding endemic zoonoses in poor regions such as those caused by Trypanosoma cruzi and Leishmania spp infections. In this scenario, it is worth highlighting a group of natural peptide molecules (AMPs and CPPs) that are promising strategies for improving therapeutic efficacy against these neglected zoonoses, avoiding the development of toxicity and resistance of conventional treatments. This review presents the novelties of these peptide molecules and their ability to cross a whole system of cell membranes, as well as to stimulate the host immune defenses or even serve as a vector of molecules. The efforts of the biotechnological sector will make it possible to overcome the limitations of antimicrobial peptides through encapsulation and functionalization methods to obtain approval for these treatments to be used in clinical programs for the eradication of Leishmaniosis and Chagas disease.

show abstract

“…LdRab5a regulates fluid-phase endocytosis, whereas LdRab5b controls receptor-mediated endocytosis in the parasite [ 52 ]. The function of LdRab5b is essential for the parasites as Rab5b knockout parasites are unable to survive in the macrophages, probably due to the unavailability of the heme from Hb [ 53 ]. We showed that Rab7 in Leishmania localizes in the late endosomes and mediates the transport of cargo from the early to the late/lysosomal compartment, such as mammalian cells [ 54 ].…”

Section: Intracellular Trafficking In Leishmaniamentioning

confidence: 99%

“…Interestingly, the HbR sequence is well conserved in different species and strains of L. amazonensis , L. infantum , L. donovani , L. major , L. turanica , L. gerbilli , L. tropica and L. enrietti, with 97 to 100% sequence identity indicating that other species of Leishmania possibly use HbR for heme acquisition [ 76 ]. In addition, immunolocalization studies demonstrate that the HbR is also present in intracellular amastigote form [ 77 ] and mediates Hb uptake in amastigotes [ 53 ]. More recently, a 40 amino acids sequence (SSEKMKQLTMYMIHEMVEGLEGRPSTVRMLPSFVYTSDPA) in the N-terminal of HbR was identified as a Hb-binding domain [ 78 ].…”

Section: Heme Acquisition Processes In Leishmaniamentioning

confidence: 99%

“…Subsequently, LdRab5b -/- null-mutant parasites are generated, and these parasites show severe growth defects and are unable to internalize Hb. However, these cells are rescued by exogenous addition of hemin in the growth medium, demonstrating that Leishmania internalizes Hb in Rab5b dependent process and generates intracellular heme by lysosomal degradation for its survival [ 53 ]. Interestingly, LdRab5b -/- parasites can infect the macrophages but are unable to survive after 96 h of infection in comparison to the normal parasite.…”

Section: Heme Acquisition Processes In Leishmaniamentioning

confidence: 99%

See 1 more Smart Citation

Hemoglobin Endocytosis and Intracellular Trafficking: A Novel Way of Heme Acquisition by Leishmania

2022

Self Cite

View full text Add to dashboard Cite

Leishmania species are causative agents of human leishmaniasis, affecting 12 million people annually. Drugs available for leishmaniasis are toxic, and no vaccine is available. Thus, the major thrust is to identify new therapeutic targets. Leishmania is an auxotroph for heme and must acquire heme from the host for its survival. Thus, the major focus has been to understand the heme acquisition process by the parasites in the last few decades. It is conceivable that the parasite is possibly obtaining heme from host hemoprotein, as free heme is not available in the host. Current understanding indicates that Leishmania internalizes hemoglobin (Hb) through a specific receptor by a clathrin-mediated endocytic process and targets it to the parasite lysosomes via the Rab5 and Rab7 regulated endocytic pathway, where it is degraded to generate intracellular heme that is used by the parasite. Subsequently, intra-lysosomal heme is initially transported to the cytosol and is finally delivered to the mitochondria via different heme transporters. Studies using different null mutant parasites showed that these receptors and transporters are essential for the survival of the parasite. Thus, the heme acquisition process in Leishmania may be exploited for the development of novel therapeutics.

show abstract

Rab5b function is essential to acquire heme from hemoglobin endocytosis for survival of Leishmania

Cited by 7 publications

References 43 publications

Identification and characterization of the hemoglobin‐binding domain of hemoglobin receptor in Leishmania

Identification and characterization of the hemoglobin‐binding domain of hemoglobin receptor in Leishmania

Neglected Zoonotic Diseases: Advances in the Development of Cell-Penetrating and Antimicrobial Peptides against Leishmaniosis and Chagas

Hemoglobin Endocytosis and Intracellular Trafficking: A Novel Way of Heme Acquisition by Leishmania

Contact Info

Product

Resources

About