Host Factor ANP32A in Avian Influenza Virus Replication and Cross-Species Adaptation: A Narrative Review

Highly pathogenic avian influenza virus undergoes continuous evolution with strengthened cross-species transmission capacity, posing a severe threat to global public health security. Host acidic nuclear phosphoprotein 32A (ANP32A) acts as a critical host cofactor for activating influenza viral RNA-dependent RNA polymerase, and plays a central role in viral replication and host adaptation. This review systematically elaborates the molecular features of ANP32A, as well as the mechanism by which its leucine-rich repeat (LRR) domain specifically binds to the polymerase basic protein 2 (PB2) subunit and its low-complexity acidic region (LCAR) interacts with polymerase acidic protein (PA) to facilitate the assembly and functional activation of viral polymerase complexes. It also summarizes the influences of species-specific sequence variations and splicing isoforms of ANP32A on the host restriction barrier of cross-species transmission. Further analyses reveal that ANP32A indirectly modulates the transcriptional levels of genes related to interferons, NF-κB and NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasomes via chromatin epigenetic modification and transcriptional resource competition, remodeling the cellular antiviral microenvironment as a nuclear transcriptional regulator. ANP32A and acidic nuclear phosphoprotein 32B (ANP32B) exert complementary functions to support viral polymerase activity, while acidic nuclear phosphoprotein 32E (ANP32E) only provides weak auxiliary effects on a small subset of mutant influenza strains with its primary physiological function centered on chromatin regulation; the three proteins jointly participate in the regulatory network of viral replication. Drawing on recent advances in cryo-electron microscopy structural biology and CRISPR/Cas9 gene-editing technologies, which are discussed narratively in this review, this review highlights the pivotal hub role of ANP32A in viral host adaptation and cross-species spillover.