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

Authors

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

Published in

Cell reports. Volume 45. Issue 10. Pages 118106. Oct 06, 2026. Epub Oct 06, 2026.

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.

PMID:
42837260
Bibliographic data and abstract were imported from PubMed on 07 Oct 2026.

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