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. 2023 Apr 25:1–17. Online ahead of print. doi: 10.1038/s41579-023-00889-z

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Fig. 2 — a, Hepatitis A (HAV) RNA (7.5 kb) contains a lengthy 5′ untranslated region with secondary structure essential for genome replication and an internal ribosomal entry site (IRES) that initiates cap-independent translation of a single long open reading frame (ORF) encoding a large polyprotein. The polyprotein is processed by the HAV protease 3C^pro into three proteins that form the capsid, VP0 (also known as 1AB; subsequently processed into VP4 (1A) and VP2 (1B)), VP3 (1C) and VP1pX (1D), and six nonstructural proteins that mediate genome replication, 2B, 2C, 3A, 3B, 3C^pro and 3D^pol. The 8-kDa pX segment is present in quasi-enveloped HAV (eHAV), but cleaved from VP1 upon loss of the membrane, and it is not present in naked HAV (nHAV)⁸. Proteomics studies show that programmed cell death 6-interacting protein (ALIX), vacuolar protein sorting-associated protein IST1 homologue (IST1, a component of the endosomal complexes required for transport (ESCRT)-III complex), and multiple charged multivesicular body proteins (CHMPs) such as CHMP1A, CHMP1B, CHMP4B and CHMP7 (also components of ESCRT-III) are physically associated with eHAV¹¹. b, Hepatitis E virus (HEV) RNA (7.2 kb) has a 5′ 7-methylguanosine (m⁷G) cap and three ORFs that are translated in a cap-dependent manner. ORF1 encodes a multifunctional polyprotein; whether this is processed into smaller proteins in infected cells is uncertain. ORF2 and ORF3 are translated from a subgenomic RNA. ORF2 encodes the capsid protein, but also produces a secreted protein from an in-frame start codon that is thought to decoy neutralizing antibody. ORF3 protein associates with membranes and recruits TSG101, a component of ESCRT-I; it is not present in nHEV^104,121,122. An additional ORF4 exists within the ORF1 coding region of genotype 1 virus (not shown). WebLogos show conserved domains in VP2 and pX^91,93 proteins of HAV and in ORF3 protein of HEV (sequences from 40 paslahepeviruses) that recruit ESCRT during capsid quasi-envelopment. Naked and quasi-enveloped virions are shown at the top of each panel at the left and right, respectively, with associated host proteins and lipids^11,22,59. EpCAM, epithelial cell adhesion molecule (or CD326 antigen); LAMP1, lysosome-associated membrane protein 1; PtSer, phosphatidylserine; TGOLN2, trans-Golgi network integral membrane protein 2.