Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a widely distributed protein belonging to the heterogeneous nuclear ribonucleoprotein (hnRNP) family, involved in RNA metabolism. It plays a fundamental role in numerous cellular processes, contributing significantly to cellular health.
Understanding hnRNP A1
hnRNP A1 is a protein that binds to RNA, specifically heterogeneous nuclear RNA (hnRNA). Structurally, hnRNP A1 is composed of two main regions: an N-terminal domain featuring two RNA recognition motifs (RRMs) and a highly flexible, glycine-rich C-terminal region. The N-terminal RRMs are crucial for its RNA binding specificity, while the C-terminal region contains an RGG box, another RNA binding domain, and a nuclear targeting sequence called M9.
While hnRNP A1 is predominantly found in the cell nucleus, it actively shuttles between the nucleus and the cytoplasm. This shuttling ability is mediated by the M9 domain, which acts as a bidirectional transport signal for both nuclear import and export. This dynamic localization allows hnRNP A1 to participate in RNA processing events occurring in both cellular compartments.
Key Functions of hnRNP A1 in the Cell
hnRNP A1 is involved in RNA splicing, a process where non-coding regions, called introns, are removed from precursor messenger RNA (pre-mRNA) and the coding regions, exons, are joined together to form mature messenger RNA (mRNA). It often acts as a splicing repressor by binding to specific sequences within exons or introns, known as exonic splicing silencers (ESSs) or intronic splicing silencers (ISSs). This binding can block the recognition of exons or promote their exclusion from the final mRNA transcript. For instance, hnRNP A1 binding to a specific sequence in the MAPT gene’s exon 10 promotes its skipping.
Beyond splicing, hnRNP A1 also plays a role in transporting mRNA from the nucleus to the cytoplasm. It associates with mRNA molecules in the nucleus and helps deliver them to the cytoplasm, where protein synthesis occurs. This transport function is facilitated by the M9 domain, which interacts with transport receptors.
Furthermore, hnRNP A1 contributes to telomere maintenance. Telomeres are protective caps at the ends of chromosomes, and their proper length is important for genomic stability. hnRNP A1 can bind to telomeric repeats, helping to unfold DNA structures like G-quadruplexes that can block telomerase, an enzyme that adds telomeric repeats. It also stimulates telomerase activity and interacts with the Shelterin protein complex, which helps cap telomeres.
hnRNP A1’s Role in Human Health and Disease
Dysregulation or mutations in hnRNP A1 have been linked to several human diseases, particularly neurodegenerative conditions and various cancers. In neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), hnRNP A1 dysfunction is a recurring theme. ALS is characterized by the progressive loss of motor neurons, leading to muscle paralysis, while FTD involves neuronal loss in the frontal and temporal lobes, causing changes in personality, behavior, and language. These two diseases often overlap clinically and genetically, and mutations in hnRNP A1, especially within its low complexity domain, have been identified in a subset of familial and sporadic cases.
The pathogenic mutations in hnRNP A1 can lead to its abnormal aggregation and mislocalization from the nucleus to the cytoplasm, forming pathological inclusions in affected tissues. This altered behavior is thought to contribute to neuronal dysfunction and loss, potentially by exacerbating protein aggregation and affecting RNA metabolism. For instance, mutant hnRNP A1 can accelerate self-polymerization and self-seeding of fibril-prone proteins.
hnRNP A1 is also implicated in various cancers, where its expression is often elevated compared to normal tissues. In lung cancer, increased hnRNP A1 expression is associated with poorer patient survival. It promotes lung cancer cell proliferation by influencing the translation of specific proteins involved in cell cycle progression. In gastric cancer, high levels of hnRNP A1 promote cell invasion by inducing epithelial-mesenchymal transition (EMT), a process where cancer cells gain migratory and invasive properties. hnRNP A1 can also function as a transcriptional co-activator in tumor progression, recognizing specific DNA structures in genes like KRAS to maintain the invasive activity of pancreatic cancer cells.