# Post-translational regulation of hepatitis B virus large envelope protein

> **NIH NIH R21** · RHODE ISLAND HOSPITAL · 2021 · $245,500

## Abstract

Project Summary/Abstract
 The large (L) envelope protein of hepatitis B virus (HBV) is essential for virion production
and infectivity, and its high intracellular level can cause liver cancer. It has extra preS1 + preS2
domains than small (S) envelope protein. Majority of the S protein is secreted as noninfectious
subviral particles (SVPs), which have been implicated in the induction of immune tolerance for
establishment of chronic HBV infection. L protein is not secreted when expressed alone. It interacts
with core particle to initiate virion morphogenesis, and recruits the S protein for virion secretion. In
doing so it also suppresses SVP secretion according to L/S protein ratio. L protein is also essential
for initiation of HBV infection by interacting with the high-affinity receptor. Despite its critical
importance in HBV biology and pathogenesis, little is known about regulation of its intracellular level
at the post-translational step. We previously found that preventing S protein expression by mutating
the initiating ATG into GCG abolished M protein, suggesting its reliance on S protein for stability.
The intracellular level of L protein was also markedly reduced despite blocked secretion. Very
recently, we discovered this particular mutant could produce a shortened and non-secreted S
protein through translation initiation from a downstream ATG. Further mutating that ATG into GCG
diminished intracellular L protein to extremely low level. Nevertheless, mutating the first and second
in-frame ATG codons in the S gene into GCG introduces amino acid substitutions in the S domain
of L protein. To verify that reduced L protein level is attributed to lost S protein expression rather
than mutations in L protein, in Aim 1 we will test the impact of mutating the S gene ATG codon into
other codons such as ATA, AAG, and TTG. The preS1 region harbors the promoter for 2.1-kb RNA
for M/S proteins, and we recently found many naturally occurring in-frame preS1 deletions
abolished S protein expression. Whether lost S protein expression at the transcriptional level also
diminishes intracellular level of shortened L protein will be determined. Aim 2 will establish the role
of core protein in sustaining L protein level and check for its synergy with S protein. Our pilot study
suggested that core protein expression was required to sustain both intracellular and extracellular
levels of L protein. In Aim 3, we will verify whether much reduced intracellular level of L protein is
attributed to accelerated degradation, and examine if providing S or core protein in trans can rescue
the L protein level. We hypothesize that during HBV virion morphogenesis, L protein is stabilized by
its molecular interaction with core particles or with S protein. The proposed studies will reveal a
novel mechanism to control L protein level at the post-translational level, which should have
therapeutic implications.

## Key facts

- **NIH application ID:** 10287803
- **Project number:** 1R21AI163819-01
- **Recipient organization:** RHODE ISLAND HOSPITAL
- **Principal Investigator:** Jisu Li
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $245,500
- **Award type:** 1
- **Project period:** 2021-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10287803

## Citation

> US National Institutes of Health, RePORTER application 10287803, Post-translational regulation of hepatitis B virus large envelope protein (1R21AI163819-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10287803. Licensed CC0.

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