The balance between nuclear import and export of NLRC5 regulates MHC class I transactivation

Baohui Zhu; Ryota Ouda; Ning An; Tsutomu Tanaka; Koichi S Kobayashi

doi:10.1016/j.jbc.2024.107205

The balance between nuclear import and export of NLRC5 regulates MHC class I transactivation

J Biol Chem. 2024 Mar 20;300(5):107205. doi: 10.1016/j.jbc.2024.107205. Online ahead of print.

Authors

Baohui Zhu¹, Ryota Ouda¹, Ning An¹, Tsutomu Tanaka², Koichi S Kobayashi³

Affiliations

¹ Department of Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
² Department of Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan.
³ Department of Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan; Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, Texas, USA. Electronic address: kskobayashi@med.hokudai.ac.jp.

Abstract

Major histocompatibility complex (MHC) class I molecules play an essential role in regulating the adaptive immune system by presenting antigens to CD8 T cells. CITA (MHC class I transactivator), also known as NLRC5 (NLR family, CARD domain-containing 5), regulates the expression of MHC class I and essential components involved in the MHC class I antigen presentation pathway. While the critical role of the nuclear distribution of NLRC5 in its transactivation activity has been known, the regulatory mechanism to determine the nuclear localization of NLRC5 remains poorly understood. In this study, a comprehensive analysis of all domains in NLRC5 revealed that the regulatory mechanisms for nuclear import and export of NLRC5 coexist and counterbalance each other. Moreover, GCN5 (general control non-repressed 5 protein), a member of HATs (histone acetyltransferases), was found to be a key player to retain NLRC5 in the nucleus, thereby contributing to the expression of MHC class I. Therefore, the balance between import and export of NLRC5 has emerged as an additional regulatory mechanism for MHC class I transactivation, which would be a potential therapeutic target for the treatment of cancer and virus-infected diseases.

Keywords: GCN5; NLRC5; acetyltransferase; antigen presentation; major histocompatibility complex (MHC); protein export; protein import.