Protein&Cell

Current Articles
2021, Volume 12, Issue 9

The hippocampus plays a crucial role in learning and memory, and its progressive deterioration with age is functionally linked to a variety of human neurodegenerative diseases. In this issue, Zhang et al. (page number 718–734) presented the first single-nucleus transcriptomic atlas of primate hippocampal aging. They revealed impaired progenitor cell division and compromised neuronal function along the neurogenesis trajectory, as well as elevated pro-inflammatory responses in the niche cells contributing to a hostile microenvironment in the aged hippocampus. Consistently, they observed a variety of new aging-associated phenotypic changes, including increased DNA damage and heterochromatin erosion with time, alongside loss of proteostasis and elevated inflammation. This may provide potential diagnostic biomarkers and therapeutic interventions against the agerelated neurodegenerative diseases.

Recollection

Origin of the Chinese word for “cell”: an unusual but wonderful idea of a mathematician

He Zhang

2021, 12(9): 671-674. doi: 10.1007/s13238-020-00790-y

[Abstract](118) [PDF 1064KB](20)

Abstract:

Commentary

Cytochrome P450 reductase (POR) as a ferroptosis fuel

Pranavi Koppula, Li Zhuang, Boyi Gan

2021, 12(9): 675-679. doi: 10.1007/s13238-021-00823-0

[Abstract](88) [PDF 409KB](15)

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Review

Higher-order assemblies in immune signaling:supramolecular complexes and phase separation

Shiyu Xia, Zhenhang Chen, Chen Shen, Tian-Min Fu

2021, 12(9): 680-694. doi: 10.1007/s13238-021-00839-6

[Abstract](136) [PDF 2414KB](22)

Abstract:
Signaling pathways in innate and adaptive immunity play vital roles in pathogen recognition and the functions of immune cells. Higher-order assemblies have recently emerged as a central principle that governs immune signaling and, by extension, cellular communication in general. There are mainly two types of higherorder assemblies:1) ordered, solid-like large supramolecular complexes formed by stable and rigid protein-protein interactions, and 2) liquid-like phaseseparated condensates formed by weaker and more dynamic intermolecular interactions. This review covers key examples of both types of higher-order assemblies in major immune pathways. By placing emphasis on the molecular structures of the examples provided, we discuss how their structural organization enables elegant mechanisms of signaling regulation.

Research articles

Single-nucleus transcriptomic landscape of primate hippocampal aging

Hui Zhang, Jiaming Li, Jie Ren, Shuhui Sun, Shuai Ma, Weiqi Zhang, Yang Yu, Yusheng Cai, Kaowen Yan, Wei Li, Baoyang Hu, Piu Chan, Guo-Guang Zhao, Juan Carlos Izpisua Belmonte, Qi Zhou, Jing Qu, Si Wang, Guang-Hui Liu

2021, 12(9): 695-716. doi: 10.1007/s13238-021-00852-9

[Abstract](186) [PDF 3407KB](55)

Abstract:
The hippocampus plays a crucial role in learning and memory, and its progressive deterioration with age is functionally linked to a variety of human neurodegenerative diseases. Yet a systematic profiling of the aging effects on various hippocampal cell types in primates is still missing. Here, we reported a variety of new aging-associated phenotypic changes of the primate hippocampus. These include, in particular, increased DNA damage and heterochromatin erosion with time, alongside loss of proteostasis and elevated inflammation. To understand their cellular and molecular causes, we established the first single-nucleus transcriptomic atlas of primate hippocampal aging. Among the 12 identified cell types, neural transiently amplifying progenitor cell (TAPC) and microglia were most affected by aging. In-depth dissection of gene-expression dynamics revealedimpairedTAPCdivisionandcompromisedneuronal function along the neurogenesis trajectory; additionally elevated pro-inflammatory responses in the aged microglia and oligodendrocyte, as well as dysregulated coagulation pathways in the aged endothelial cells may contribute to a hostile microenvironment for neurogenesis. This rich resource for understanding primate hippocampal aging may provide potential diagnostic biomarkers and therapeutic interventions against age-related neurodegenerative diseases.

Host metabolism dysregulation and cell tropism identification in human airway and alveolar organoids upon SARS-CoV-2 infection

Rongjuan Pei, Jianqi Feng, Yecheng Zhang, Hao Sun, Lian Li, Xuejie Yang, Jiangping He, Shuqi Xiao, Jin Xiong, Ying Lin, Kun Wen, Hongwei Zhou, Jiekai Chen, Zhili Rong, Xinwen Chen

2021, 12(9): 717-733. doi: 10.1007/s13238-020-00811-w

[Abstract](98) [PDF 7299KB](26)

Abstract:
The coronavirus disease 2019 (COVID-19) pandemic is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is spread primary via respiratory droplets and infects the lungs. Currently widely used cell lines and animals are unable to accurately mimic human physiological conditions because of the abnormal status of cell lines (transformed or cancer cells) and species differences between animals and humans. Organoids are stem cell-derived selforganized three-dimensional culture in vitro and model the physiological conditions of natural organs. Here we showed that SARS-CoV-2 infected and extensively replicated in human embryonic stem cells (hESCs)-derived lung organoids, including airway and alveolar organoids which covered the complete infection and spread route for SARS-CoV-2 within lungs. The infected cells were ciliated, club, and alveolar type 2 (AT2) cells, which were sequentially located from the proximal to the distal airway and terminal alveoli, respectively. Additionally, RNA-seq revealed early cell response to virus infection including an unexpected downregulation of the metabolic processes, especially lipid metabolism, in addition to the well-known upregulation of immune response. Further, Remdesivir and a human neutralizing antibody potently inhibited SARS-CoV-2 replication in lung organoids. Therefore, human lung organoids can serve as a pathophysiological model to investigate the underlying mechanism of SARS-CoV-2 infection and to discover and test therapeutic drugs for COVID-19.

Letters

Understanding the phase separation characteristics of nucleocapsid protein provides a new therapeutic opportunity against SARS-CoV-2

Dan Zhao, Weifan Xu, Xiaofan Zhang, Xiaoting Wang, Yiyue Ge, Enming Yuan, Yuanpeng Xiong, Shenyang Wu, Shuya Li, Nian Wu, Tingzhong Tian, Xiaolong Feng, Hantao Shu, Peng Lang, Jingxin Li, Fengcai Zhu, Xiaokun Shen, Haitao Li, Pilong Li, Jianyang Zeng

2021, 12(9): 734-740. doi: 10.1007/s13238-021-00832-z

[Abstract](191) [PDF 2243KB](53)

Abstract:

Indiscriminate ssDNA cleavage activity of CRISPR-Cas12a induces no detectable off-target effects in mouse embryos