AhR-Siglec-15 axis regulates lysosomal Ca2+ release for sonic hedgehog medulloblastoma growth via TRPML1

Sonic hedgehog subgroup medulloblastoma (SHH-MB), an aggressive pediatric brain tumor that originates from granule neuron precursors, faces the challenge of poor treatment owing to its unclear molecular mechanisms. Here, we show that sialic acid-binding immunoglobulin-like receptor 15 (Siglec-15), an immunosuppressive membrane protein, is upregulated and mediates SHH-MB growth through its translocation to the lysosomal membrane. We found that SHH-MB cells use the cation-independent mannose 6-phosphate receptor (CI-MPR) to transport Siglec-15 from the trans-Golgi network (TGN) to lysosomes, where Siglec-15 induces lysosomal Ca2+ release by interacting with mucolipin TRP cation channel 1 (TRPML1), leading to the nuclear translocation of the transcription factor EB (TFEB). Blockade of Siglec-15, TRPML1 or TFEB hinders SHH-MB growth in vitro and in vivo. Importantly, aryl hydrocarbon receptor (AhR), a cytoplasmic transcription factor, upregulates Siglec-15 expression. AhR inhibition by CH-223191 or StemRegenin 1 (SR1) achieved therapeutic efficacy against orthotopic SHH-MB xenografts in mice. These findings reveal an essential role for the AhR-siglec-15 axis in SHH-MB development, providing a potential strategy for SHH-MB treatment.

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Publication Details

Journal
Protein & Cell
Published
2025-11-14
DOI
https://doi.org/10.1093/procel/pwaf100
Primary Topic
Hedgehog Signaling Pathway Studies
Type
article
Field-Weighted Citation Impact
0.00

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article

AhR-Siglec-15 axis regulates lysosomal Ca2+ release for sonic hedgehog medulloblastoma growth via TRPML1

Li Min Zhou, Yabo Zhou, Nannan Zhou, Jiadi Lv et al.
Protein & Cell
Hedgehog Signaling Pathway Studies
article

AhR-Siglec-15 axis regulates lysosomal Ca2+ release for sonic hedgehog medulloblastoma growth via TRPML1

Li Min Zhou, Yabo Zhou, Nannan Zhou, Jiadi Lv, Jie Chen, Xu Sun, Bo Huang, Zhenfeng Wang, Qiaoying Zhu, Guihong Zhang, Jinyan Liu, Wei-Min Tong, Shunshun Li, Dianheng Wang
article en

Abstract

Sonic hedgehog subgroup medulloblastoma (SHH-MB), an aggressive pediatric brain tumor that originates from granule neuron precursors, faces the challenge of poor treatment owing to its unclear molecular mechanisms. Here, we show that sialic acid-binding immunoglobulin-like receptor 15 (Siglec-15), an immunosuppressive membrane protein, is upregulated and mediates SHH-MB growth through its translocation to the lysosomal membrane. We found that SHH-MB cells use the cation-independent mannose 6-phosphate receptor (CI-MPR) to transport Siglec-15 from the trans-Golgi network (TGN) to lysosomes, where Siglec-15 induces lysosomal Ca2+ release by interacting with mucolipin TRP cation channel 1 (TRPML1), leading to the nuclear translocation of the transcription factor EB (TFEB). Blockade of Siglec-15, TRPML1 or TFEB hinders SHH-MB growth in vitro and in vivo. Importantly, aryl hydrocarbon receptor (AhR), a cytoplasmic transcription factor, upregulates Siglec-15 expression. AhR inhibition by CH-223191 or StemRegenin 1 (SR1) achieved therapeutic efficacy against orthotopic SHH-MB xenografts in mice. These findings reveal an essential role for the AhR-siglec-15 axis in SHH-MB development, providing a potential strategy for SHH-MB treatment.

Protein & Cell
Shenyang Medical College (CN), Capital Medical University (CN), Anhui Medical University (CN), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Peking Union Medical College Hospital (CN), First Hospital of China Medical University (CN), Beijing YouAn Hospital (CN), First Affiliated Hospital of Zhengzhou University (CN), Institute of Basic Medical Sciences of the Chinese Academy of Medical Sciences, China Medical University (CN)
National Natural Science Foundation of China, Chinese Academy of Medical Sciences, National Key Research and Development Program of China
Openalex Percentile: Top 68%
Hedgehog Signaling Pathway Studies
DOIOpen Access PDFOpenAlex
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