# Critical protein interactions for piRNA biogenesis

> **NIH NIH R03** · MICHIGAN STATE UNIVERSITY · 2024 · $157,000

## Abstract

PROJECT SUMMARY
P-element induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are ~24-34 nt non-coding RNAs that have
been discovered in diverse species. Repressing the expression of transposable elements via piRNAs represents
a critical defense mechanism for germ cells to maintain genomic integrity. The piRNA biogenesis largely occurs
at nuage, the amorphous electron-dense granules with no limiting membrane in the cytoplasm. One specific type
of nuage, intermitochondrial cement (IMC), is identified with uniquely clustered mitochondria and
ribonucleoproteins as “cementing material” in embryonic germ cells, postnatal spermatogonia, and early-stage
spermatocytes. RNA-binding proteins such as PIWI family members are critical for piRNA biogenesis at IMC.
Disrupting IMC formation or removing RNA-binding proteins from IMC often blocks spermatogenesis and impairs
male fertility. Notably, none of the PIWI proteins possesses mitochondrial localization signal (MLS), and thus
they must rely on other proteins to be recruited to mitochondria or to functionally communicate with IMC. However,
it remains a knowledge gap in how mitochondria recruit PIWI proteins to form IMC for piRNA biogenesis. To fill
in this gap, in this R03 project, we will reveal how ASZ1, a mitochondrion-localized germ cell-specific protein,
recruits PIWI proteins to IMC for piRNA biogenesis (Aim 1) and subsequently impacts male germ cell
development (Aim 2). Impact: Germ cells are essential carriers to pass genomic information across generations.
This process requires properly generated piRNAs to maintain germline DNA integrity. By unveiling essential
protein interactions at IMC and defining their roles in IMC construction, piRNA biogenesis, and germ cell
development, this project will generate novel knowledge about how the piRNA processing machinery is
assembled to maintain genomic integrity, and thus critically inform the mechanistic causes of male infertility
related to piRNA biogenesis for targeted therapies. Findings from this project may also lead to a novel strategy
for developing non-hormonal male contraceptives.

## Key facts

- **NIH application ID:** 10884024
- **Project number:** 1R03HD110627-01A1
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Yuan Wang
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $157,000
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10884024

## Citation

> US National Institutes of Health, RePORTER application 10884024, Critical protein interactions for piRNA biogenesis (1R03HD110627-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10884024. Licensed CC0.

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