Abstract
The hnRNP A/B family of proteins is canonically central to cellular RNA metabolism, but due to their highly conserved nature, the functional differences between hnRNP A1, A2/B1, A0, and A3 are often overlooked. In this review, we explore and identify the shared and disparate homeostatic and disease-related functions of the hnRNP A/B family proteins, highlighting areas where the proteins have not been clearly differentiated. Herein, we provide a comprehensive assembly of the literature on these proteins. We find that there are critical gaps in our grasp of A/B proteins' alternative splice isoforms, structures, regulation, and tissue and cell-type-specific functions, and propose that future mechanistic research integrating multiple A/B proteins will significantly improve our understanding of how this essential protein family contributes to cell homeostasis and disease.
Highlights
As with the other aspects of A1 and A2/B1 responses to stress, SGs themselves can be dysregulated. It is most apparent in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and multiple sclerosis (MS), where disease-associated genetic and somatic mutations in the prion-like domain (PrLD) of A1 and A2/B1 result in their increased cytoplasmic localization, exacerbated and expedited response to stress stimuli, and delayed or inhibited granule disassembly [51,52,93,187,188,189,190]
The G-rich strand is the scaffold for a “cap”-like structure that prevents the cell from recognizing telomeres as damaged DNA, and since Tanaka et al [263] noted that A3 binding prevents nuclease degradation of telomeres, while Travina et al [267] recently found that A3 interacts with TRF2 (TTAGG repeat factor 2), they propose that A3 serves as a component of that protective cap
A/B proteins are all closely related, share significant sequence homology, and have highly conserved domain architecture and structures, yet they carry out separate functions using distinct mechanisms
Summary
While the hnRNP A/B proteins share significant amino acid sequence identity (Figure 1) and are all involved in multiple aspects of cellular RNA metabolism, there is clear evolutionary evidence (Figure 2), supported by experimental data, that each protein fills a distinct role in cellular homeostasis. All four proteins share a high N-terminal amino acid identity (Figure 1C), but their C-terminal domains are more divergent in amino acid sequence and protein:protein interactors, facilitating their below-described distinct roles in the cell. To our knowledge, this is the first review to comprehensively address hnRNPs A0 and. Black and grey highlights indicate exons exSequence alignment for the full-length isoforms of each family protein, from. 3) [34,35]
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