Genome-wide CRISPR screening identified hemojuvelin as a non-neuronal receptor for the botulinum neurotoxin serotypes A and C.

IF 7.7 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2026-10-27 Epub Date: 2026-10-06 DOI:10.1016/j.celrep.2026.118106

Wantong Ma, Bo Liu, Jingjing Gao, Rong Nie, Ziye Liu, Wenrui Wang, Yu Wang, Guihua Ning, Chengmu Zhao, Yudong Wang, Xinrui Yue, Dang Ding, Xinyao Ma, Jinghan He, Xiaoru Wang, Fuwei Qi, Yali Liu, Fudi Wang, Xin Wang, Dejuan Zhi, Dongsheng Wang

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Abstract

Botulinum neurotoxins (BoNTs) enter cells primarily through neuronal receptors and gangliosides. However, the mechanism that enables their specific accumulation at neuromuscular junctions (NMJs) remains poorly understood. In this study, a genome-wide CRISPR-Cas9 screen identifies hemojuvelin (HJV), a membrane protein abundant in skeletal muscle, as a non-neuronal receptor for BoNT/A and BoNT/C. Knockout and rescue experiments show that HJV mediates toxin binding by a direct interaction between its C-terminal region (residues 155-393) and the toxin WY loop within the receptor-binding domain (HCR). In mice, HJV knockout markedly reduces toxin enrichment on the sarcolemma and significantly attenuates toxin sensitivity such as digital paralysis and lethality. Thus, HJV captures these toxins on the muscle sarcolemma, establishing a critical prerequisite for efficient recognition and internalization by neuronal receptors at NMJs. These findings further refine the entry mechanism of BoNTs in vivo and offer actionable insights for treating BoNT intoxication and for optimizing their clinical applications.

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全基因组CRISPR筛选鉴定了haemjuvelin是肉毒杆菌神经毒素血清型a和C的非神经元受体。

肉毒杆菌神经毒素（BoNTs）主要通过神经元受体和神经节苷进入细胞。然而，使它们在神经肌肉连接点（NMJs）特异性积累的机制仍然知之甚少。在这项研究中，全基因组CRISPR-Cas9筛选鉴定了骨骼肌中丰富的膜蛋白血少年蛋白（HJV）作为BoNT/ a和BoNT/C的非神经元受体。基因敲除和修复实验表明，HJV通过其c端区（残基155-393）与受体结合域（HCR）内的毒素WY环之间的直接相互作用介导毒素结合。在小鼠中，敲除HJV可显著减少肌膜上的毒素富集，并显著减轻毒素敏感性，如手指麻痹和致死率。因此，HJV在肌肌膜上捕获这些毒素，为NMJs的神经元受体有效识别和内化建立了关键的先决条件。这些发现进一步完善了BoNT在体内的进入机制，并为治疗BoNT中毒和优化其临床应用提供了可行的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.