BMI1 induces ubiquitination and protein degradation of Nod‐like receptor family CARD domain containing 5 and suppresses human leukocyte antigen class I expression to induce immune escape in non‐small cell lung cancer

Abstract

The Nod-like receptor (NLR) family CARD domain containing 5 (NLRC5) has been reported as an activator of human leukocyte antigen (HLA) class I that is responsible for immune activity in cancer treatment. This work focuses on the role of BMI1 proto-oncogene (BMI1) in the NLRC5-HLA class I axis and in immune escape in nonsmall cell lung cancer (NSCLC). First, immunoblot analysis and/or reverse transcription-quantitative polymerase chain reaction were performed, which identified decreased NLRC5 and HLA class I levels in NSCLC tissues and cell lines. NSCLCs were co-cultured with activated CD8 + T cells. Overexpression of NLRC5 in NSCLC cells elevated the expression of HLA class I and increased the activity of T cells and IL-2 production, and it reduced the PD-1/PD-L1 levels. The ubiquitination and immunoprecipitation assays confirmed that BMI1 bound to NLRC5 to induce is ubiquitination and protein degradation. Downregulation of BMI1 in NSCLC cells elevated NLRC5 and HLA class I levels, and consequently promoted T cell activation and decreased PD-1/PD-L1 levels in the co-culture system. However, overexpression of BMI1 in cells led to inverse trends. In summary, this study demonstrates that BMI1 induces ubiquitination and protein degradation of NLRC5 and suppresses HLA class I expression, which potentially helps immune escape in NSCLC.

Orientia tsutsugamushiAnk5 directs ubiquitination and proteasomal degradation of NLRC5 to inhibit major histocompatibility complex class I expression

“…BMI1, an E3 ubiquitin ligase component of polycomb repressive complex 1, binds NLRC5 to induce its ubiquitination and degradation, which reduces MHC class I surface expression and CD8 + T cell activation. 114 Of more than 1900 bacterial genomes, the Ikeda chromosome encodes the fifth-largest number of Anks, accounting for 2.4% of its content. By comparison, ank genomic content for Homo sapiens, Mus musculus, and the average of all obligate intracellular bacteria except Chlamydia species, which do not have any ank genes, is 3.1%, 1.7%, and 0.8%, respectively.…”

“…The remarkable similarity between Ank5 and BMI1 mechanisms of action is a striking example of convergent evolution in that both an intracellular pathogen and oncogene co-opt ubiquitination/proteasomal degradation to subvert the NLRC5-MHC class I axis. As exemplified for BMI1, 114 this strategy likely enables Ikeda and other O. tsutsugamushi strains that express Ank5 to evade CD8+ T cell-mediated immunity and additional NLRC5-dependent immune responses. By unveiling NLRC5 as a target for microbial immunomodulation, this study advances understanding of how O. tsutsugamushi and potentially other intracellular pathogens maximize survival in their intracellular niches.…”

“…BMI1, an E3 ubiquitin ligase component of polycomb repressive complex 1, binds NLRC5 to induce its ubiquitination and degradation, which reduces MHC class I surface expression and CD8 + T cell activation. 114…”

Advances of E3 ligases in lung cancer

“…E3 ligases can influence immune cell function, including the expression and stability of immune checkpoint molecules, leading to regulating tumor immune escape and anti-tumor immune responses [ 58 , 59 ]. Beta-transducin repeat containing E3 ubiquitin-protein ligase (βTrCP), also known as FBW1A, promotes LUAD tumor growth by interacting with, ubiquitinating and mediating proteasomal degradation of YAP [ 60 ].…”

The roles of protein ubiquitination in tumorigenesis and targeted drug discovery in lung cancer

“…When ubiquitination is in an pathological state, the activated biological process will not only promote cancer progression, but also induce neoplastic immune escape ( 102 ). BMI1 could promote ubiquitination and degradation of NLRC5, and inhibits HLA class I, which might contribute to the immune escape of NSCLC ( 103 ). PAQR4 is overexpressed in LC.…”