2021 Vol. 12, No. 4

Cholesterol metabolism is essential in regulating the antitumor efficacy of CD8+ T cells, but the mechanisms by which the tumor microenvironment reprograms CD8+ T cell cholesterol metabolism remain unknown. Yuan et al. found the low-density lipoprotein receptor (LDLR) is essential for the CD8+T cell antitumor activities. Beside the canonical role on LDL uptake, LDLR can interact with TCR complex and regulate TCR recycling and signaling. PCSK9, a regulator of LDLR, can bind LDLR and prevent the recycling of LDLR and TCR to the plasma membrane. Inhibition of PCSK9 can enhance the antitumor activity of CD8+ T cells, indicating PCSK9/LDLR axis as a potential target for cancer immunotherapy.

Debao Wang, the founder of nucleic acid biology and industry in People's Republic of China
Zhongliang Ma, Xianyi Wang, Yanli Li
2021, 12(4): 237-239. doi: 10.1007/s13238-020-00777-9
Research articles
Potentiating CD8+ T cell antitumor activity by inhibiting PCSK9 to promote LDLRmediated TCR recycling and signaling
Juanjuan Yuan, Ting Cai, Xiaojun Zheng, Yangzi Ren, Jingwen Qi, Xiaofei Lu, Huihui Chen, Huizhen Lin, Zijie Chen, Mengnan Liu, Shangwen He, Qijun Chen, Siyang Feng, Yingjun Wu, Zhenhai Zhang, Yanqing Ding, Wei Yang
2021, 12(4): 240-260. doi: 10.1007/s13238-021-00821-2
Metabolic regulation has been proven to play a critical role in T cell antitumor immunity. However, cholesterol metabolism as a key component of this regulation remains largely unexplored. Herein, we found that the low-density lipoprotein receptor (LDLR), which has been previously identified as a transporter for cholesterol, plays a pivotal role in regulating CD8+ T cell antitumor activity. Besides the involvement of cholesterol uptake which is mediated by LDLR in T cell priming and clonal expansion, we also found a non-canonical function of LDLR in CD8+ T cells:LDLR interacts with the T-cell receptor (TCR) complex and regulates TCR recycling and signaling, thus facilitating the effector function of cytotoxic T-lymphocytes (CTLs). Furthermore, we found that the tumor microenvironment (TME) downregulates CD8+ T cell LDLR level and TCR signaling via tumor cellderived proprotein convertase subtilisin/kexin type 9 (PCSK9) which binds to LDLR and prevents the recycling of LDLR and TCR to the plasma membrane thus inhibits the effector function of CTLs. Moreover, genetic deletion or pharmacological inhibition of PCSK9 in tumor cells can enhance the antitumor activity of CD8+ T cells by alleviating the suppressive effect on CD8+ T cells and consequently inhibit tumor progression. While previously established as a hypercholesterolemia target, this study highlights PCSK9/LDLR as a potential target for cancer immunotherapy as well.
Histone deacetylase 3 promotes innate antiviral immunity through deacetylation of TBK1
Jie-lin Tang, Qi Yang, Chong-hui Xu, He Zhao, Ya-ling Liu, Can-yu Liu, Yuan Zhou, Dong-wei Gai, Rong-juan Pei, Yun Wang, Xue Hu, Bo Zhong, Yan-yi Wang, Xin-wen Chen, Ji-zheng Chen
2021, 12(4): 261-278. doi: 10.1007/s13238-020-00751-5
TANK-binding kinase 1 (TBK1), a core kinase of antiviral pathways, activates the production of interferons (IFNs). It has been reported that deacetylation activates TBK1; however, the precise mechanism still remains to be uncovered. We show here that during the early stage of viral infection, the acetylation of TBK1 was increased, and the acetylation of TBK1 at Lys241 enhanced the recruitment of IRF3 to TBK1. HDAC3 directly deacetylated TBK1 at Lys241 and Lys692, which resulted in the activation of TBK1. Deacetylation at Lys241 and Lys692 was critical for the kinase activity and dimerization of TBK1 respectively. Using knockout cell lines and transgenic mice, we confirmed that a HDAC3 null mutant exhibited enhanced susceptibility to viral challenge via impaired production of type I IFNs. Furthermore, activated TBK1 phosphorylated HDAC3, which promoted the deacetylation activity of HDAC3 and formed a feedback loop. In this study, we illustrated the roles the acetylated and deacetylated forms of TBK1 play in antiviral innate responses and clarified the post-translational modulations involved in the interaction between TBK1 and HDAC3.
POST1/C12ORF49 regulates the SREBP pathway by promoting site-1 protease maturation
Jian Xiao, Yanni Xiong, Liu-Ting Yang, Ju-Qiong Wang, Zi-Mu Zhou, Le-Wei Dong, Xiong-Jie Shi, Xiaolu Zhao, Jie Luo, Bao-Liang Song
2021, 12(4): 279-296. doi: 10.1007/s13238-020-00753-3
Sterol-regulatory element binding proteins (SREBPs) are the key transcriptional regulators of lipid metabolism. The activation of SREBP requires translocation of the SREBP precursor from the endoplasmic reticulum to the Golgi, where it is sequentially cleaved by site-1 protease (S1P) and site-2 protease and releases a nuclear form to modulate gene expression. To search for new genes regulating cholesterol metabolism, we perform a genome-wide CRISPR/Cas9 knockout screen and find that partner of site-1 protease (POST1), encoded by C12ORF49, is critically involved in the SREBP signaling. Ablation of POST1 decreases the generation of nuclear SREBP and reduces the expression of SREBP target genes. POST1 binds S1P, which is synthesized as an inactive protease (form A) and becomes fully mature via a two-step autocatalytic process involving forms B'/B and C'/C. POST1 promotes the generation of the functional S1P-C'/C from S1P-B'/B (canonical cleavage) and, notably, from S1P-A directly (non-canonical cleavage) as well. This POST1-mediated S1P activation is also essential for the cleavages of other S1P substrates including ATF6, CREB3 family members and the α/β- subunit precursor of N-acetylglucosamine-1-phosphotransferase. Together, we demonstrate that POST1 is a cofactor controlling S1P maturation and plays important roles in lipid homeostasis, unfolded protein response, lipoprotein metabolism and lysosome biogenesis.
The nuclear bodies formed by histone demethylase KDM7A
Hui Ming, Qianfeng Wang, Yuwen Zhang, Luzhang Ji, Lu Cheng, Xiangru Huo, Zixiang Yan, Zhexiao Liu, Yongjun Dang, Bo Wen
2021, 12(4): 297-304. doi: 10.1007/s13238-020-00783-x
Single-cell RNA-Seq analysis identified kidney progenitor cells from human urine
Yujia Wang, Yu Zhao, Zixian Zhao, Dandan Li, Hao Nie, Yufen Sun, Xiaobei Feng, Ting Zhang, Yu Ma, Jing Nie, Guangyan Cai, Xiangmei Chen, Wei Zuo
2021, 12(4): 305-312. doi: 10.1007/s13238-020-00816-5
Correction to: Human cytomegalovirus DNA and immediate early protein 1/2 are highly associated with glioma and prognosis
Le Wen, Fei Zhao, Yong Qiu, Shuang Cheng, Jin-Yan Sun, Wei Fang, Simon Rayner, Michael A. McVoy, Xing-Jun Jiang, Qiyi Tang, Fang-Cheng Li, Fei Hu, Min-Hua Luo
2021, 12(4): 313-313. doi: 10.1007/s13238-020-00787-7