Bauer Sarah, Aeissen Vanessa, Bubeck Alena M, Kienes Ioannis, Ellwanger Kornelia, Scheurenbrand Mona, Rexhepi Fjolla, Ramanathan Sheela, Rosenstiel Philip, Fricke W Florian, Kufer Thomas A
Department of Immunology, Institute of Nutritional Medicine, University of Hohenheim, 70599 Stuttgart, Germany.
Department of Microbiome and Applied Bioinformatics, Institute of Nutritional Science, University of Hohenheim, 70599 Stuttgart, Germany.
iScience. 2023 Mar 2;26(4):106313. doi: 10.1016/j.isci.2023.106313. eCollection 2023 Apr 21.
Nucleotide-binding and oligomerization domain containing 5 (NLRC5) is the key transcriptional regulator of major histocompatibility (MHC) class I genes. Recent observations suggest a role for NLRC5 in metabolic traits and in transcriptional regulation beyond MHC class I genes. To understand the function of NLRC5 in metabolic disease, we subjected mice to high-fat diet (HFD) feeding. Female mice presented with higher weight gain and more adipose tissue (AT) compared to wild-type (WT) animals. Mechanistically, we demonstrate that NLRC5 enhanced the expression of peroxisome proliferator-activated receptor (PPAR) γ target genes in human cells. We identify Sin3A and negative elongation factor (NELF) B as two novel NLRC5 interaction partners and show that Sin3A partly modulates the synergistic transcriptional effect of NLRC5 on PPARγ. Collectively, we show that NLRC5 contributes to weight gain in mice, which involves transcriptional enhancement of PPARγ targets by NLRC5 that is co-regulated by Sin3A.
含核苷酸结合和寡聚化结构域5（NLRC5）是主要组织相容性复合体（MHC）I类基因的关键转录调节因子。最近的观察结果表明，NLRC5在代谢特征以及MHC I类基因以外的转录调控中发挥作用。为了了解NLRC5在代谢疾病中的功能，我们用高脂饮食（HFD）喂养小鼠。与野生型（WT）动物相比，雌性小鼠体重增加更多，脂肪组织（AT）更多。从机制上讲，我们证明NLRC5增强了人细胞中过氧化物酶体增殖物激活受体（PPAR）γ靶基因的表达。我们鉴定出Sin3A和负性延伸因子（NELF）B是NLRC5的两个新的相互作用伙伴，并表明Sin3A部分调节NLRC5对PPARγ的协同转录作用。总体而言，我们表明NLRC5导致小鼠体重增加，这涉及NLRC5对PPARγ靶标的转录增强，而Sin3A共同调节这一过程。
