RESUMO
The presentation of antigenic peptides by major histocompatibility complex (MHC) class I and class II molecules is crucial for activation of the adaptive immune system. The nucleotide-binding domain and leucine-rich repeat receptor family members CIITA and NLRC5 function as the major transcriptional activators of MHC class II and class I gene expression, respectively. Since the identification of NLRC5 as the master regulator of MHC class I and class-I-related genes, there have been major advances in understanding the function of NLRC5 in infectious diseases and cancer. Here, we discuss the biological significance and mechanism of NLRC5-dependent MHC class I expression.
Assuntos
Imunidade Adaptativa , Antígenos de Histocompatibilidade Classe I/metabolismo , Inflamassomos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias/metabolismo , Transativadores/metabolismo , Animais , Regulação da Expressão Gênica , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Inflamassomos/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias/genética , Neoplasias/imunologia , Transdução de Sinais , Evasão Tumoral , Microambiente TumoralRESUMO
Major histocompatibility complex (MHC) class I and class II molecules play critical roles in the activation of the adaptive immune system by presenting antigens to CD8+ and CD4+ T cells, respectively. Although it has been well known that CIITA (MHC class II transactivator), an NLR (nucleotide-binding domain, leucine-rich-repeat containing) protein, as a master regulator of MHC class II gene expression, the mechanism of MHC class I gene transactivation was unclear. Recently, another NLR protein, NLRC5 (NLR family, CARD domain-containing 5), was identified as an MHC class I transactivator (CITA). NLRC5 is a critical regulator for the transcriptional activation of MHC class I genes and other genes involved in the MHC class I antigen presentation pathway. CITA/NLRC5 plays a crucial role in human cancer immunity through the recruitment and activation of tumor killing CD8+ T cells. Here, we discuss the molecular function and mechanism of CITA/NLRC5 in the MHC class I pathway and its role in cancer.
Assuntos
Regulação da Expressão Gênica , Antígenos de Histocompatibilidade Classe I/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias/imunologia , Transativadores/metabolismo , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias/genética , Neoplasias/metabolismo , Transativadores/genéticaRESUMO
Cancer cells need to escape immune surveillance for successful tumor growth. Loss of MHC class I has been described as a major immune evasion strategy in many cancers. MHC class I transactivator (CITA), NLRC5 [nucleotide-binding domain and leucine-rich repeats containing (NLR) family, caspase activation and recruitment domain (CARD) domain containing 5], is a key transcription coactivator of MHC class I genes. Recent genetic studies have revealed that NLRC5 is a major target for cancer immune evasion mechanisms. The reduced expression or activity of NLRC5 caused by promoter methylation, copy number loss, or somatic mutations is associated with defective MHC class I expression, impaired cytotoxic T cell activation, and poor patient prognosis. Here, we review the role of NLRC5 in cancer immune evasion and the future prospects for cancer research.
Assuntos
Vigilância Imunológica , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Neoplasias/imunologia , Animais , Biomarcadores Tumorais/imunologia , Regulação Neoplásica da Expressão Gênica , Genes MHC Classe I , Humanos , PrognósticoRESUMO
Cancer cells develop under immune surveillance, thus necessitating immune escape for successful growth. Loss of MHC class I expression provides a key immune evasion strategy in many cancers, although the molecular mechanisms remain elusive. MHC class I transactivator (CITA), known as "NLRC5" [NOD-like receptor (NLR) family, caspase recruitment (CARD) domain containing 5], has recently been identified as a critical transcriptional coactivator of MHC class I gene expression. Here we show that the MHC class I transactivation pathway mediated by CITA/NLRC5 constitutes a target for cancer immune evasion. In all the 21 tumor types we examined, NLRC5 expression was highly correlated with the expression of MHC class I, with cytotoxic T-cell markers, and with genes in the MHC class I antigen-presentation pathway, including LMP2/LMP7, TAP1, and ß2-microglobulin. Epigenetic and genetic alterations in cancers, including promoter methylation, copy number loss, and somatic mutations, were most prevalent in NLRC5 among all MHC class I-related genes and were associated with the impaired expression of components of the MHC class I pathway. Strikingly, NLRC5 expression was significantly associated with the activation of CD8(+) cytotoxic T cells and patient survival in multiple cancer types. Thus, NLRC5 constitutes a novel prognostic biomarker and potential therapeutic target of cancers.
Assuntos
Apresentação de Antígeno , Biomarcadores Tumorais/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias/imunologia , Transativadores/imunologia , Ativação Transcricional/imunologia , Evasão Tumoral , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/imunologia , Biomarcadores Tumorais/genética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/imunologia , Feminino , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Proteínas de Neoplasias/genética , Neoplasias/genética , Neoplasias/mortalidade , Neoplasias/patologia , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/imunologia , Transativadores/genética , Microglobulina beta-2/genética , Microglobulina beta-2/imunologiaRESUMO
Major histocompatibility complex (MHC) class I and class II molecules play essential roles in the development and activation of the human adaptive immune system. An NLR protein, CIITA (MHC class II transactivator) has been recognized as a master regulator of MHC class II gene expression, albeit knowledge about the regulatory mechanism of MHC class I gene expression had been limited. Recently identified MHC class I transactivator (CITA), or NLRC5, also belongs to the NLR protein family and constitutes a critical regulator for the transcriptional activation of MHC class I genes. In addition to MHC class I genes, CITA/NLRC5 induces the expression of ß2 -microglobulin, TAP1 and LMP2, essential components of the MHC class I antigen presentation pathway. Therefore, CITA/NLRC5 and CIITA are transcriptional regulators that orchestrate the concerted expression of critical components in the MHC class I and class II pathways, respectively. © 2016 BioFactors, 42(4):349-357, 2016.
Assuntos
Genes MHC Classe I , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Animais , Expressão Gênica , Regulação da Expressão Gênica , HumanosRESUMO
MreB is a cytoskeletal protein, which is responsible for maintaining proper cellular morphology and is essential for cell survival. Likewise, penicillin-binding protein 5 (PBP5) helps in maintaining cell shape, though non-essential for survival. The contradicting feature of these two proteins paves the way for this study, wherein we attempt to draw a relation on the nature of distribution of MreB in PBP deletion mutants. The study revealed that the uniform MreB helices/patches were destabilized/disturbed at the zone of deformities of the PBP mutants, whereas the helical patterns were retained at the regions maintaining a rod shape. We interpret that MreB remains functional irrespective of its distribution being misguided by the aberrant shapes of PBP mutants.
