# Role of LC3B in Host Defense against Human Herpesvirus 8 Lytic Replication

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2024 · $204,688

## Abstract

ABSTRACT
Autophagy is an evolutionarily conserved cellular housekeeping system that mediates the removal of damaged
or excess organelles and harmful protein aggregates. Selective autophagy targets specific substrates and is
mediated mainly by autophagy receptors, which contain an LC3-interacting region and can therefore bind directly
to the mammalian ATG8 (ATG8) family of proteins, including MAP1LC3A (LC3A), LC3B, LC3C, GABARAP,
GABARAPL1, and GABARAPL2. Viral xenophagy (virophagy) is a form of selective autophagy targeting finally
assembled virions or components thereof and is believed to be the first line of host defense against virus infection.
While several different mechanisms of virophagy to some viruses have recently been proposed, it is largely
unknown how antiviral selective autophagy is activated by infection by human gammaherpesviruses, including
human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus (KSHV). HHV-8 is the
etiological agent of at least three human malignancies, Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL),
and multicentric Castleman’s disease in immunodeficient individuals with HIV-1 infection or those taking
immunosuppressant drugs. Two infection stages of HHV-8 in the host, latency and lytic replication, are causally
associated with HHV-8 pathogenesis. To comprehensively assess the functional involvement of selective
autophagy in HHV-8 infection, we generated the cell lines of BCBL-1, an HHV-8-infected PEL cell, that are
knocked out for each gene of ATG8 proteins. While any of the single gene knockout (KO) of the ATG8 family did
not affect the growth of latently infected cells, a loss of LC3B, but not the other members, promoted productive
virus replication, potentially through selective upregulation of the late lytic gene expression and suppression of
type III interferon (IFN) expression. In addition, we found that intracellular viral DNA (vDNA) content and nuclear
size significantly increased in lytic LC3B KO cells. LC3B overexpression significantly reduced the nuclear size
of lytic cells, but this effect was reversed by autophagy inhibition. Moreover, the formation of nuclear blebs,
indicative of nucleophagy, was reduced in lytic LC3B KO cells. Therefore, we hypothesize that LC3B may play
a crucial role in the host antiviral response to lytic replication by mediating the nuclear export of nascent vDNA
for autophagic degradation and type III IFN expression. To test this hypothesis, we will first custom-develop
methods to detect nuclear exported (cytoplasmic and virion-free) vDNAs and identify the molecular mechanisms
of LC3B-mediated nuclear export of vDNAs by performing mutagenesis and structure-activity relationship studies
and examining the interaction between LC3B and Ku70. Secondly, we will assess the functional effects of the
LC3B/Ku70-mediated vDNA export in reactivation-induced innate immune response and lytic replication. The
proposed study should broaden our knowledge o...

## Key facts

- **NIH application ID:** 10887045
- **Project number:** 1R21AI177806-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Young Bong Choi
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $204,688
- **Award type:** 1
- **Project period:** 2024-01-16 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10887045

## Citation

> US National Institutes of Health, RePORTER application 10887045, Role of LC3B in Host Defense against Human Herpesvirus 8 Lytic Replication (1R21AI177806-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10887045. Licensed CC0.

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