Protein&Cell

Current Articles
2023, Volume 14, Issue 9

Lipophagy, the selective engulfment of lipid droplets (LDs) by autophagosomes for lysosomal degradation, is critical to lipid and energy homeostasis. Pu et al. found that ORP8 is a lipophagy receptor that plays a key role in cellular lipid metabolism. The results show that the lipid transfer protein ORP8 is located on LDs and mediates the encapsulation of LDs by autophagosomal membranes. This function of ORP8 is independent of its lipid transporter activity and is achieved through direct interaction with phagophore-anchored LC3/GABARAPs. Upon lipophagy induction, ORP8 has increased localization on LDs and is phosphorylated by AMPK, thereby enhancing its affinity for LC3/ GABARAPs. Deletion of ORP8 or interruption of ORP8-LC3/GABARAP interaction results in accumulation of LDs and increased intracellular triglyceride. Overexpression of ORP8 alleviates LD and triglyceride deposition in the liver of ob/ob mice, and Osbpl8^-/- mice exhibit liver lipid clearance defects.

Recollection

Zhu Xi: a pioneer of experimental biology

Yujing Qian, Xiazhao Yu, Yangqing Sun, Qun Xie Ge Liang, Gaiping Bai

2023, 14(9): 629-631. doi: 10.1093/procel/pwac055

[Abstract](69) [PDF 303KB](16)

Abstract:

Commentary

Join the club: ORP8 is a lipophagy receptor

Zheng Wang, Hong Zhang

2023, 14(9): 632-634. doi: 10.1093/procel/pwad005

[Abstract](39) [PDF 656KB](4)

Abstract:

Review

Recent progress and challenges in the treatment of spinal cord injury

Ting Tian, Sensen Zhang, Maojun Yang

2023, 14(9): 635-652. doi: 10.1093/procel/pwad003

[Abstract](41) [PDF 4598KB](3)

Abstract:
Spinal cord injury (SCI) disrupts the structural and functional connectivity between the higher center and the spinal cord, resulting in severe motor, sensory, and autonomic dysfunction with a variety of complications. The pathophysiology of SCI is complicated and multifaceted, and thus individual treatments acting on a specific aspect or process are inadequate to elicit neuronal regeneration and functional recovery after SCI. Combinatory strategies targeting multiple aspects of SCI pathology have achieved greater beneficial effects than individual therapy alone. Although many problems and challenges remain, the encouraging outcomes that have been achieved in preclinical models offer a promising foothold for the development of novel clinical strategies to treat SCI. In this review, we characterize the mechanisms underlying axon regeneration of adult neurons and summarize recent advances in facilitating functional recovery following SCI at both the acute and chronic stages. In addition, we analyze the current status, remaining problems, and realistic challenges towards clinical translation. Finally, we consider the future of SCI treatment and provide insights into how to narrow the translational gap that currently exists between preclinical studies and clinical practice. Going forward, clinical trials should emphasize multidisciplinary conversation and cooperation to identify optimal combinatorial approaches to maximize therapeutic benefit in humans with SCI.

Research Articles

ORP8 acts as a lipophagy receptor to mediate lipid droplet turnover

Maomao Pu, Wenhui Zheng, Hongtao Zhang, Wei Wan, Chao Peng, Xuebo Chen, Xinchang Liu, Zizhen Xu, Tianhua Zhou, Qiming Sun, Dante Neculai, Wei Liu

2023, 14(9): 653-667. doi: 10.1093/procel/pwac063

[Abstract](116) [PDF 24794KB](30)

Abstract:
Lipophagy, the selective engulfment of lipid droplets (LDs) by autophagosomes for lysosomal degradation, is critical to lipid and energy homeostasis. Here we show that the lipid transfer protein ORP8 is located on LDs and mediates the encapsulation of LDs by autophagosomal membranes. This function of ORP8 is independent of its lipid transporter activity and is achieved through direct interaction with phagophore-anchored LC3/GABARAPs. Upon lipophagy induction, ORP8 has increased localization on LDs and is phosphorylated by AMPK, thereby enhancing its affinity for LC3/GABARAPs. Deletion of ORP8 or interruption of ORP8-LC3/GABARAP interaction results in accumulation of LDs and increased intracellular triglyceride. Overexpression of ORP8 alleviates LD and triglyceride deposition in the liver of ob/ob mice, and Osbpl8^-/- mice exhibit liver lipid clearance defects. Our results suggest that ORP8 is a lipophagy receptor that plays a key role in cellular lipid metabolism.

Longitudinal proteomic investigation of COVID-19 vaccination

Yingrui Wang, Qianru Zhu, Rui Sun, Xiao Yi, Lingling Huang, Yifan Hu, Weigang Ge, Huanhuan Gao, Xinfu Ye, Yu Song, Li Shao, Yantao Li, Jie Li, Tiannan Guo, Junping Shi

2023, 14(9): 668-682. doi: 10.1093/procel/pwad004

[Abstract](29) [PDF 9967KB](2)

Abstract:
Although the development of COVID-19 vaccines has been a remarkable success, the heterogeneous individual antibody generation and decline over time are unknown and still hard to predict. In this study, blood samples were collected from 163 participants who next received two doses of an inactivated COVID-19 vaccine (CoronaVac^®) at a 28-day interval. Using TMT-based proteomics, we identified 1,715 serum and 7,342 peripheral blood mononuclear cells (PBMCs) proteins. We proposed two sets of potential biomarkers (seven from serum, five from PBMCs) at baseline using machine learning, and predicted the individual seropositivity 57 days after vaccination (AUC=0.87). Based on the four PBMC's potential biomarkers, we predicted the antibody persistence until 180 days after vaccination (AUC=0.79). Our data highlighted characteristic hematological host responses, including altered lymphocyte migration regulation, neutrophil degranulation, and humoral immune response. This study proposed potential blood-derived protein biomarkers before vaccination for predicting heterogeneous antibody generation and decline after COVID-19 vaccination, shedding light on immunization mechanisms and individual booster shot planning.

METTL14 is a chromatin regulator independent of its RNA N⁶-methyladenosine methyltransferase activity

Xiaoyang Dou, Lulu Huang, Yu Xiao, Chang Liu, Yini Li, Xinning Zhang, Lishan Yu, Ran Zhao, Lei Yang, Chuan Chen, Xianbin Yu, Boyang Gao, Meijie Qi, Yawei Gao, Bin Shen, Shuying Sun, Chuan He, Jun Liu

2023, 14(9): 683-697. doi: 10.1093/procel/pwad009

[Abstract](87) [PDF 6881KB](19)

Abstract:
METTL3 and METTL14 are two components that form the core heterodimer of the main RNA m⁶A methyltransferase complex (MTC) that installs m⁶A. Surprisingly, depletion of METTL3 or METTL14 displayed distinct effects on stemness maintenance of mouse embryonic stem cell (mESC). While comparable global hypo-methylation in RNA m⁶A was observed in Mettl3 or Mettl14 knockout mESCs, respectively. Mettl14 knockout led to a globally decreased nascent RNA synthesis, whereas Mettl3 depletion resulted in transcription upregulation, suggesting that METTL14 might possess an m⁶A-independent role in gene regulation. We found that METTL14 colocalizes with the repressive H3K27me3 modification. Mechanistically, METTL14, but not METTL3, binds H3K27me3 and recruits KDM6B to induce H3K27me3 demethylation independent of METTL3. Depletion of METTL14 thus led to a global increase in H3K27me3 level along with a global gene suppression. The effects of METTL14 on regulation of H3K27me3 is essential for the transition from self-renewal to differentiation of mESCs. This work reveals a regulatory mechanism on heterochromatin by METTL14 in a manner distinct from METTL3 and independently of m⁶A, and critically impacts transcriptional regulation, stemness maintenance, and differentiation of mESCs.

Letters

Structural basis of INTAC-regulated transcription