bims-toxgon 2024-02-04 papers

Issue of 2024–02–04
five papers selected by
Lakesh Kumar, BITS Pilani

Front Cell Infect Microbiol. 2023 ;13 1332146

Dissecting EXP2 sequence requirements for protein export in malaria parasites.

Ethan L Pitman, Natalie A Counihan, Joyanta K Modak, Mrittika Chowdury, Paul R Gilson, Chaille T Webb, Tania F de Koning-Ward.

Apicomplexan parasites that reside within a parasitophorous vacuole harbor a conserved pore-forming protein that enables small-molecule transfer across the parasitophorous vacuole membrane (PVM). In Plasmodium parasites that cause malaria, this nutrient pore is formed by EXP2 which can complement the function of GRA17, an orthologous protein in Toxoplasma gondii. EXP2, however, has an additional function in Plasmodium parasites, serving also as the pore-forming component of the protein export machinery PTEX. To examine how EXP2 can play this additional role, transgenes that encoded truncations of EXP2, GRA17, hybrid GRA17-EXP2, or EXP2 under the transcriptional control of different promoters were expressed in EXP2 knockdown parasites to determine which could complement EXP2 function. This revealed that EXP2 is a unique pore-forming protein, and its protein export role in P. falciparum cannot be complemented by T. gondii GRA17. This was despite the addition of the EXP2 assembly strand and part of the linker helix to GRA17, which are regions necessary for the interaction of EXP2 with the other core PTEX components. This indicates that the body region of EXP2 plays a critical role in PTEX assembly and/or that the absence of other T. gondii GRA proteins in P. falciparum leads to its reduced efficiency of insertion into the PVM and complementation potential. Altering the timing and abundance of EXP2 expression did not affect protein export but affected parasite viability, indicating that the unique transcriptional profile of EXP2 when compared to other PTEX components enables it to serve an additional role in nutrient exchange.

Keywords: EXP2; GRA17; PTEX; Plasmodium; nutrient exchange; protein export

DOI: https://doi.org/10.3389/fcimb.2023.1332146

Exp Mol Med. 2024 Feb 01.

Exploring the potential of Toxoplasma gondii in drug development and as a delivery system.

Chanjin Yoon, Yu Seong Ham, Woo Jin Gil, Chul-Su Yang.

Immune-mediated inflammatory diseases are various groups of conditions that result in immune system disorders and increased cancer risk. Despite the identification of causative cytokines and pathways, current clinical treatment for immune-mediated inflammatory diseases is limited. In addition, immune-mediated inflammatory disease treatment can increase the risk of cancer. Several previous studies have demonstrated that Toxoplasma gondii manipulates the immune response by inhibiting or stimulating cytokines, suggesting the potential for controlling and maintaining a balanced immune system. Additionally, T. gondii also has the unique characteristic of being a so-called "Trojan horse" bacterium that can be used as a drug delivery system to treat regions that have been resistant to previous drug delivery therapies. In this study, we reviewed the potential of T. gondii in drug development and as a delivery system through current research on inflammation-regulating mechanisms in immune-mediated inflammatory diseases.

DOI: https://doi.org/10.1038/s12276-024-01165-7

Curr Opin Microbiol. 2024 Feb 01. pii: S1369-5274(24)00006-7. [Epub ahead of print]78 102430

Hungry for control: metabolite signaling to chromatin in Plasmodium falciparum.

Ruth Lappalainen, Manish Kumar, Manoj T Duraisingh.

The human malaria parasite Plasmodium falciparum undergoes a complex life cycle in two hosts, mammalian and mosquito, where it is constantly subjected to environmental changes in nutrients. Epigenetic mechanisms govern transcriptional switches and are essential for parasite persistence and proliferation. Parasites infecting red blood cells are auxotrophic for several nutrients, and mounting evidence suggests that various metabolites act as direct substrates for epigenetic modifications, with their abundance directly relating to changes in parasite gene expression. Here, we review the latest understanding of metabolic changes that alter the histone code resulting in changes to transcriptional programmes in malaria parasites.

DOI: https://doi.org/10.1016/j.mib.2024.102430

Shock. 2024 Jan 08.

Acetyl-CoA production by octanoic acid alleviates acute compartment syndrome-induced skeletal muscle injury through regulating mitophagy.

Xiangkang Jiang, Shaoyun Liu, Jingyuan Yang, Yao Lin, Wenbin Zhang, Jiawei Tao, Huiming Zhong, Jiefeng Xu, Mao Zhang.

BACKGROUND: Treatment of acute compartment syndrome (ACS) induced skeletal muscle injury remains a challenge. Previous studies have shown that octanoic acid is a promising treatment for ACS owing to its potential ability to regulate metabolic/epigenetic pathways in ischemic injury. The present study was designed to investigate the efficacy and underlying mechanism of octanoic acid in ACS-induced skeletal muscle injury.
METHODS: In this study, we established a saline infusion ACS rat model. Subsequently, we assessed the protective effects of sodium octanoate (NaO, sodium salt of octanoic acid) on ACS-induced skeletal muscle injury. Afterward, the level of acetyl-CoA and histone acetylation in the skeletal muscle tissue were quantified. Moreover, we investigated the activation of the AMPK pathway and the occurrence of mitophagy in the skeletal muscle tissue. Lastly, we scrutinized the expression of proteins associated with mitochondrial dynamics in the skeletal muscle tissue.
RESULTS: The administration of NaO attenuated muscle inflammation, alleviating oxidative stress and muscle edema. Moreover, NaO treatment enhanced muscle blood perfusion, leading to the inhibition of apoptosis-related skeletal muscle cell death following ACS. Additionally, NaO demonstrated the ability to halt skeletal muscle fibrosis and enhance the functional recovery of muscle post-ACS. Further analysis indicates that NaO treatment increases the acetyl-CoA level in muscle and the process of histone acetylation by acetyl-CoA. Lastly, we found NaO treatment exerts a stimulatory impact on the activation of the AMPK pathway, thus promoting mitophagy and improving mitochondrial dynamics.
CONCLUSION: Our findings indicate that octanoic acid may ameliorate skeletal muscle injury induced by ACS. Its protective effects may be attributed to the promotion of acetyl-CoA synthesis and histone acetylation within the muscular tissue, as well as its activation of the AMPK-related mitophagy pathway.

DOI: https://doi.org/10.1097/SHK.0000000000002304

Pharmacol Ther. 2024 Jan 28. pii: S0163-7258(24)00010-X. [Epub ahead of print]254 108590

A novel therapeutic target for kidney diseases: Lessons learned from starvation response.

Kosuke Yamahara, Mako Yasuda-Yamahara, Shinji Kume.

The prevalence of chronic kidney disease (CKD) is increasing worldwide, making the disease an urgent clinical challenge. Caloric restriction has various anti-aging and organ-protective effects, and unraveling its molecular mechanisms may provide insight into the pathophysiology of CKD. In response to changes in nutritional status, intracellular nutrient signaling pathways show adaptive changes. When nutrients are abundant, signals such as mechanistic target of rapamycin complex 1 (mTORC1) are activated, driving cell proliferation and other processes. Conversely, others, such as sirtuins and AMP-activated protein kinase, are activated during energy scarcity, in an attempt to compensate. Autophagy, a cellular self-maintenance mechanism that is regulated by such signals, has also been reported to contribute to the progression of various kidney diseases. Furthermore, in recent years, ketone bodies, which have long been considered to be detrimental, have been reported to play a role as starvation signals, and thereby to have renoprotective effects, via the inhibition of mTORC1. Therefore, in this review, we discuss the role of mTORC1, which is one of the most extensively studied nutrient-related signals associated with kidney diseases, autophagy, and ketone body metabolism; and kidney energy metabolism as a novel therapeutic target for CKD.

Keywords: Autophagy; CKD; Ketone body; Starvation response; mTORC1

DOI: https://doi.org/10.1016/j.pharmthera.2024.108590