Hnrnpa1, short for heterogeneous nuclear ribonucleoprotein A1, is an RNA-binding protein involved in multiple biological processes. It participates in mRNA processing, such as RNA splicing, and is associated with pathways related to lipid and glucose metabolism, cell growth, and neurodegeneration. Genetic models, like gene knockout (KO) or conditional knockout (CKO) mouse models, are valuable tools to study its functions [1-3].

In adipocyte-specific Hnrnpa1 knockout mice, depletion of Hnrnpa1 in adipocytes promoted macrophage infiltration, upregulated pro-inflammatory and fibrosis genes in white adipose tissue (WAT) of obese mice, leading to exacerbated insulin sensitivity, glucose tolerance, and hepatic steatosis. Mechanistically, Hnrnpa1 interacted with Ccl2 and regulated its mRNA stability [1]. In breast, colorectal, and prostate cancer cells, PRMT4/5/7-mediated arginine methylation of Hnrnpa1 regulated its binding to RNA and alternative splicing events. Inhibition of these methyltransferases suppressed cancer cell growth [2]. Mutations in the prion-like domain of Hnrnpa1 in families were associated with inherited degeneration affecting muscle, brain, motor neuron, and bone, and in one case of familial amyotrophic lateral sclerosis (ALS). The pathogenic mutations accelerated the formation of self-seeding fibrils, promoted excess incorporation of Hnrnpa1 into stress granules, and formed cytoplasmic inclusions in animal models [3].

In summary, Hnrnpa1 is crucial for mRNA processing and plays important roles in lipid and glucose metabolism, cancer cell growth, and neurodegenerative diseases. Studies using KO/CKO mouse models have revealed its functions in obesity-related metabolic dysfunction, cancer, and neurodegeneration, providing insights into potential therapeutic targets for these diseases [1-3].

References:

1. Li, Xiaoya, Su, Yingying, Xu, Yiting, Yang, Ying, Bao, Yuqian. . Adipocyte-Specific Hnrnpa1 Knockout Aggravates Obesity-Induced Metabolic Dysfunction via Upregulation of CCL2. In Diabetes, 73, 713-727. doi:10.2337/db23-0609. https://pubmed.ncbi.nlm.nih.gov/38320300/

2. Li, Wen-Juan, He, Yao-Hui, Yang, Jing-Jing, Ye, Feng, Liu, Wen. 2021. Profiling PRMT methylome reveals roles of hnRNPA1 arginine methylation in RNA splicing and cell growth. In Nature communications, 12, 1946. doi:10.1038/s41467-021-21963-1. https://pubmed.ncbi.nlm.nih.gov/33782401/

3. Kim, Hong Joo, Kim, Nam Chul, Wang, Yong-Dong, Shorter, James, Taylor, J Paul. 2013. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. In Nature, 495, 467-73. doi:10.1038/nature11922. https://pubmed.ncbi.nlm.nih.gov/23455423/