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Revealing the Role of Liquid-Liquid Phase Separation in Plasmodium falciparum Transcriptional Regulation

Award Number: R21AI193904
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/06/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Revealing the Role of Liquid-Liquid Phase Separation in Plasmodium falciparum Transcriptional Regulation - PROJECT SUMMARY In 2023 alone, malaria resulted in 263 million cases and 597,000 deaths, presenting a severe global health burden that predominantly affects children and pregnant women. Malaria is caused by Plasmodium parasites that are transmitted by Anopheline mosquitoes. Artemisinin-based combination therapies (ACT) have been the main treatment for malaria since 2006, with a 90% success rate, but emerging resistance threatens the efficacy of ACTs. Research into new antimalarial drugs is desperately needed, especially to identify drugs that target parasite-specific processes. One of the distinguished features of P. falciparum, the most virulent of the human malaria parasites, is its genome structure which is highly A/T rich (>80% in coding regions) and about twice as large as that of Saccharomyces cerevisiae, which encodes roughly the same number of genes. This difference in genome size can mostly be attributed to the fact that asparagine (Asn) repeat sequences are inserted into many P. falciparum proteins. Asn repeat sequences can form intrinsically disordered regions (IDRs) in proteins, but the cellular function of these IDRs remains unknown despite being conserved across geographically isolated clinical isolates. Given that Asn-rich sequences are more prone to form toxic protein aggregates in cells, we hypothesize that P. falciparum Asn-rich IDRs can induce protective protein aggregation through liquid-liquid phase separation (LLPS). In this study, we will elucidate the impact of Asn-rich repeats on the physical properties and transcriptional regulatory mechanisms of Apicomplexan Apetala 2 (ApiAP2) transcription factors, where these repeats are highly prevalent. ApiAP2 proteins are conserved across Plasmodium species and regulate gene expression at all stages of parasite development and differentiation. Their essential regulatory roles and the lack of mammalian homologs make ApiAP2 proteins candidate therapeutic targets, however, the detailed mechanisms of ApiAP2 protein gene regulation needs to be further elucidated. All ApiAP2 proteins contain long stretches of homo- and hetero-polymeric Asn repeats, and 26 of the 30 known ApiAP2 proteins contain over 30% IDRs that are almost exclusively homopolymeric Asn repeats. In Aim 1, we will characterize the role of the Asn- rich IDRs from ApiAP2 proteins, by screening short, recombinant protein regions from ApiAP2 proteins for aggregation or LLPS using recombinant proteins and overexpression in mammalian cell systems in parallel. Key regions identified will be deleted from the parasite genome using gene editing. The impact on gene expression and growth phenotypes of the transgenic parasites will be determined. In Aim 2, we will investigate the effect of knocking down the chaperone Pf Hsp110c, which is the major chaperone reported to reverse aggregation in P. falciparum. The impact of Pf Hsp110 function on global proteostasis will be assessed using cellular thermal shift assays (CETSA) coupled with proteomics upon knockdown of the chaperone and using an inhibitor of Hsp110. Overall, this proposed study will provide new insights into the function and regulation of the Asn-rich regions of critical transcription factors of P. falciparum and reveal possible new strategies for therapeutic intervention.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $196,625 )
2026	2026	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	000	1	8/6/2026	NEW	$196,625
														Subtotal = $196,625

Grand Total All Awards = $196,625

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Revealing the Role of Liquid-Liquid Phase Separation in Plasmodium falciparum Transcriptional Regulation

Award Number: R21AI193904

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/06/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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