NIH grant: The "hidden" proteins in Aedes aegypti (1R21AI202145-01)

retained text

NIH grant 1R21AI202145-01: The "hidden" proteins in Aedes aegypti
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Zhijian Jake Tu. Award: $208641.
Start: 2026-07-16T00:00:00.
Abstract
Aedes aegypti is a major vector of dengue, chikungunya, yellow fever, and Zika viruses. The global
incidence of dengue increased significantly in recent decades, directly impacting the US and US
territories. No specific treatment for dengue exists and vaccine options are limited. Current prevention
depends mainly on effective vector control, which is hindered by increasing insecticide-resistance. Novel
strategies to control these devastating diseases, informed by a better understanding of mosquito biology,
are being actively explored. Omics-enabled research and effective application of modern genetic
methods have significantly improved our understanding of mosquito biology, potentially leading to new
targets and/or novel approaches for controlling mosquito-borne infectious diseases. However, an
important and prevalent component of the proteome known as the microproteins have been largely
“hidden” from genome annotations and thus ignored. The advent of Ribo-seq, a technique that sequences
ribosome protected fragments, resulted in the discovery of thousands of small open reading frames
(sORFs) engaged with actively translating ribosomes. These sORF-encoded microproteins represent a
rapidly growing treasure of the proteome that plays significant roles in various aspects of biology including
development, physiology, and metabolism. A significant portion of the sORF-encoded microproteins
represent de novo inventions which may be adaptive and confer lineage-specific functions. Long non-
coding RNAs (LncRNAs) are a major source of these “hidden” microproteins. We have recently identified
LncRNAs in Ae. aegypti that show strong evidence of protein-coding based on ribosome protected
fragments and/or evolutionary signatures. We will pursue two specific aims: 1) Discover LncRNA-
encoded microproteins in Ae. aegypti using systematic and complementary approaches; 2) Determine
the function of selected microproteins in Ae. aegypti male reproduction. The proposed research is
significant to basic biology as it has the potential to uncover >1000 “hidden” proteins in Ae. aegypti. These
“hidden” proteins can lead to new targets for the control of mosquito-borne diseases as they are often
restricted to certain mosquito lineages and the study of microprotein function in male reproduction is
relevant to genetic control programs. The proposed research will have a broad impact beyond Ae.
aegypti, as a list of well-curated and experimentally supported sORFs and the tools and methods
developed in this project will help identify and characterize microproteins in other mosquito lineages or
other arthropod vectors including ticks. The proposed research will also open doors to research into other
“hidden” non-canonical ORFs and provide valuable resources for future investigations of translation
regulation, potentially bridging a gap between transcriptomics and proteomics.

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