{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The AP3B1 gene encodes the ubiquitously expressed β‐subunit of the adaptor protein complex‐3 (AP‐3), a key component in directing transmembrane cargo from the trans‐Golgi network and endosomes to lysosome‐related organelles (LROs) such as melanosomes, platelet dense granules, and lysosomes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " This trafficking function is essential not only for the proper biogenesis of specialized organelles but also for processes such as the initiation of macroautophagy in amino acid‐starved cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In humans, loss‐of‐function mutations in AP3B1 disrupt the assembly and function of the AP‐3 complex, leading to Hermansky–Pudlak syndrome type 2 (HPS2). This syndrome is characterized by hypopigmentation (owing to impaired melanosome formation), a bleeding diathesis resulting from deficient platelet dense granules, and immunological defects such as reduced natural killer and cytotoxic T‐cell function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Moreover, aberrant trafficking of key enzymes—for example, neutrophil elastase—has been linked to conditions like cyclic neutropenia, underscoring the critical role of AP3B1 in neutrophil granule formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Post‐translational modifications further modulate AP3B1 function. For instance, IP₇–mediated pyrophosphorylation of AP3B1 regulates its interaction with the kinesin motor protein Kif3A, thereby influencing the intracellular trafficking processes that are exploited during the assembly and release of virus‐like particles in HIV‐1 and henipaviruses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, AP3B1 expression is subject to post‐transcriptional regulation; it has been identified as a target of miR‐9 in hepatocellular carcinoma, suggesting that deregulation of its expression may contribute to tumor progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Recent studies also implicate AP3B1 variants in modulating immune and inflammatory responses. Germline variants in AP3B1 have been associated with severe cytokine storms in COVID‐19 patients, further highlighting the gene’s role in regulating immune homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " In the context of viral infections, deficiencies in AP3B1 impair proper localization of HIV‐1 Gag at the plasma membrane, thereby compromising viral assembly and release"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ", and it also interacts with other transporters, such as MRP4 in platelets, to influence their intracellular distribution."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Animal models have reinforced the importance of AP3B1. For example, “pearl” mice bearing Ap3b1 mutations exhibit marked ocular hypopigmentation due to defects in melanosome maturation and altered tyrosinase trafficking"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", and additional studies in AP3B1‐deficient lung tissues have revealed mitochondrial dysfunction and compensatory metabolic changes that may contribute to pulmonary fibrosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, AP3B1 is pivotal for intracellular vesicular trafficking and organelle biogenesis. Its proper function is essential for pigmentation, hemostasis, immune cell function, and even viral particle assembly. Disruption of AP3B1 leads to a spectrum of clinical phenotypes—from bleeding disorders and immunodeficiency in HPS2 to altered inflammatory responses and potential contributions to oncogenesis—demonstrating its multifaceted role in cellular physiology."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Curtis Huttenhower, Erin M Haley, Matthew A Hibbs, et al. 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