{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nC19orf66, also known as Shiftless (SHFL), is an interferon‐stimulated gene that has emerged as a broad‐spectrum antiviral effector. Its expression is induced in response to interferon signaling during infection by diverse pathogens, including dengue virus, Zika virus, hepatitis C virus, Japanese encephalitis virus, hepatitis B virus, and human immunodeficiency virus, as well as during infection by herpesviruses such as Kaposi’s sarcoma‐associated herpesvirus. In these studies, upregulation of SHFL was associated with a marked reduction in viral replication, underscoring its clinical relevance in antiviral defense mechanisms."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMechanistically, SHFL interferes with viral gene expression through multiple pathways. In one mode of action, SHFL impairs viral protein synthesis by binding viral RNAs and interacting with host mRNA‐binding proteins, thereby inhibiting the translation process required for virus propagation. Additionally, SHFL has been shown to directly reduce the efficiency of programmed ribosomal frameshifting and stop‐codon readthrough events—critical steps for the proper expression of viral polyproteins in pathogens such as HIV-1, coronaviruses, and cardioviruses. In the case of Japanese encephalitis virus, SHFL inhibits the production of the NS1′ protein through disruption of the -1 ribosomal frameshift mechanism."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurther expanding its antiviral repertoire, SHFL also modulates host cell processes. During Kaposi’s sarcoma‐associated herpesvirus infection, SHFL targets key early viral regulatory proteins and alters RNA–protein dynamics by affecting cytoplasmic RNA granule formation, notably triggering the disassembly of processing bodies—cellular structures involved in RNA turnover. This multifaceted interference with both viral and host RNA metabolism highlights SHFL’s integral role in the innate immune response."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Youichi Suzuki, Wei-Xin Chin, Qi'En Han, et al. 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