Beyond phosphorylation: Putative roles of post-translational modifications in plasmodium sexual stages

Post-translational modifications (PTMs) allow proteins to regulate their structure, localisation and function in response to cell intrinsic and environmental signals. The diversity and number of modifications on proteins increase the complexity of cellular proteomes by orders of magnitude. Several proteomic and molecular studies have revealed an abundance of PTMs in malaria parasite proteome, where mediators of PTMs play crucial roles in parasite pathogenesis and transmission. In this article, we discuss recent findings in asexual stages of ten diverse PTMs and investigate whether these proteins are expressed in sexual stages. We discovered 25–50 % of proteins exhibiting post-translational modifications in asexual stages are also expressed in sexual stage gametocytes. Moreover we analyse the function of the modified proteins shared with the gametocyte proteome and try to encourage the scientific community to investigate the roles of diverse PTMs beyond phosphorylation in sexual stages which could not only reveal unique aspects of parasite biology, but also uncover new avenues for transmission blocking. 1. Introduction Malaria maintains a high global disease burden, threatening the health of millions of people. There were ~229 million cases of malaria worldwide in 2019, resulting in 409,000 deaths [1]. Malaria is caused by apicomplexan parasites of the Plasmodium genus, and Plasmodium fal-ciparum accounts for the highest global morbidity and mortality [1]. Most cases of malaria can be treated effectively with artemisinin-based combination therapy (ACT), however resistance to ACT is increasing and thus the need for new therapies is growing. Completion of the parasite’s life cycle requires both a vertebrate host (asexual stage) where it causes disease and a mosquito vector (sexual stage) which is essential for parasite transmission. To successfully eradicate malaria, it is essential to develop both curative and transmission blocking strategies. Few approved anti-malarials prevent parasite transmission [2], and to develop new transmission blocking therapeutics we have to improve our understanding of sexual stages. Plasmodium parasites are transmitted by the female Anopheles mosquito. Upon ingestion during a mosquito bloodmeal, specialised transmission-competent parasites (male and fe-male gametocyte cells) respond to rapid environmental changes in the mosquito gut where tight regulation of the parasite’s DNA replication, protein translation, cell morphological changes, and energy metabolism is essential for the parasite’s life-cycle transition into the vector (Fig. 1). During host-to-vector transition, the parasite faces the challenge of rapidly responding and adapting to a vastly different and hostile mos-quito gut environment. In eukaryotes, response to environmental stimuli are often regulated by post-translational modifications of effector pro-teins. Not only do PTMs on proteins exponentially expand the functional outputs from a gene, the dynamicity conferred by these modifications permit quick responses to changing environments. The modification of proteins can lead to changes in activity, relocalisation, degradation and recruitment of interacting partners. PTMs can be addition of chemical groups (e.g. phosphorylation, acetylation, methylation, S-nitrosylation), addition of polypeptides (ubiquitylation, SUMOylation), addition of complex groups (glycosylation, prenylation, myristoylation) and pro-teolytic cleavage. Chemical modification of proteins usually occurs at low stoichiometry creating a significant challenge for PTM identifica-tion. Advances in tools for enrichment of specific PTMs and develop-ment of powerful mass spectrometry has significantly increased our knowledge of the prevalence and dynamics of PTMs in Plasmodium. However a majority of the studies have focussed on the asexual blood stages of the parasite and phosphorylation is the sole PTM of non-histone proteins examined in sexual stage gametocytes [3,4]. Accordingly, beyond phosphorylation, the possible function of PTMs in transmission * Corresponding author. E-mail address: [email protected] (N. Philip). Contents lists available at ScienceDirect Molecular & Biochemical Parasitology journal homepage: www.elsevier.com/locate/molbiopara https://doi.org/10.1016/j.molbiopara.2021.111406 Received 27 January 2021; Received in revised form 7 July 2021; Accepted 22 July 2021