Exclusive expression of proteasome subunit β5t in the human thymic cortex

Abstract

The ubiquitin-proteasome pathway, which degrades intracellular proteins, is involved in numerous cellular processes, including the supply of immunocompetent peptides to the antigen presenting machinery. Proteolysis by proteasomes is conducted by three ␤ subunits, ␤1, ␤2, and ␤5, of the 20S proteasome. Recently, a novel ␤ subunit expressed exclusively in cortical thymic epithelial cells was discovered in mice. This subunit, designated ␤5t, is a component of the thymoproteasome, a specialized type of proteasomes implicated in thymic positive selection. In this study, we show that, like its mouse counterpart, human ␤5t is expressed exclusively in the thymic cortex. Human ␤5t was expressed in approximately 80% of cortical thymic epithelial cells and some cortical dendritic cells. Human ␤5t was incorporated into proteasomes with two other catalytically active ␤ subunits ␤1i and ␤2i, forming 20S proteasomes with subunit compositions characteristic of thymoproteasomes. The present study demonstrates, for the first time, the existence of thymoproteasomes in the human thymic cortex, indicating that thymoproteasome function is likely conserved between humans and mice. (Blood. 2009; 113:5186-5191)

Aging and Immune Function: Molecular Mechanisms to Interventions

“…Additionally, when cells are stimulated with pro-inflammatory cytokines, most of the constitutive proteasomes in the 20S catalytic core are replaced by immuno-proteasomes subunits b5i, b2i, and b1i, affecting the peptide production for antigen presentation. Recent reports demonstrate that cortical thymic epithelial cells selectively express a type of proteasome known as the thymoproteasome in place of b5i, called b5t (128,245,371). This subunit of the proteasome appears to be necessary for positive selection in the thymus.…”

The Proteasome: From Basic Mechanisms to Emerging Roles

“…This new subunit was also determined to have thymus-specific expression in humans. 68 The molecular mechanism underlying thymusspecific expression of β5t is unknown, but it is plausible that the transcriptional factor Foxn1 is responsible for this unique expression because β5t expression is impaired in the thymus of Foxn1-deficient nude mouse embryos. 69 Intriguingly, β5t and the immunosubunits β1i and β2i, but not their standard counterparts β1 and β2, are incorporated into the vertebrate-specific alternative 20S proteasome, which we named the "thymoproteasome" because of its thymus-specific expression (Fig.…”

A human PSMB11 variant affects thymoproteasome processing and CD8+ T cell production

“…We previously showed that β5t-containing thymoproteasome is specifically expressed in cTECs in mice and humans (2,7,9) and is essential for the optimal positive selection of functionally competent CD8 + T cells in mice (2,4,6). In order to explore the function of β5t in humans, we surveyed the NCBI public database for variations in the human PSMB11 genome sequence and found a number of PSMB11 single nucleotide variants that potentially affect the amino acid sequence of human β5t protein (Supplemental Table 1; supplemental material available online with this article; https://doi.org/10.1172/ jci.insight.93664DS1).…”

“…β5t deficiency in mice leads to the aberrant positive selection of CD8 + T cells, which are reduced in cellularity and are defective in TCR-mediated immune responses (4)(5)(6). β5t in humans is encoded by PSMB11 in chromosome 14 and is also detectable specifically in cTECs (7,8). However, the function of β5t-containing thymoproteasome in humans is unknown.…”