2. Academic Validation
  3. FUS Selectively Facilitates circRNAs Packing into Small Extracellular Vesicles within Hypoxia Neuron

FUS Selectively Facilitates circRNAs Packing into Small Extracellular Vesicles within Hypoxia Neuron

  • Adv Sci (Weinh). 2024 Jun 26:e2404822. doi: 10.1002/advs.202404822.
Jiankun Zang 1 2 3 4,  Yousheng Wu 1 3 4,  Xuanlin Su 1 3 4,  Kaiwei Cai 1 3 4,  Man Ke 1 3 4,  Niu He 1 4,  Huili Zhu 1 4,  Zefeng Tan 2,  Jielin Zhu 5,  Wensheng He 5,  Min Peng 1 3 4,  Shiqing Zhang 6,  Hongcheng Mai 7,  Anding Xu 1 3 4,  Dan Lu 1 3 4
Affiliations

Affiliations

  • 1 Department of Neurology and Stroke Center, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, 510632, China.
  • 2 Department of Neurology, The First People's Hospital of Foshan, Foshan, 528000, China.
  • 3 Clinical Neuroscience Institute, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China.
  • 4 Key Lab of Guangzhou Basic and Translational Research of Pan-vascular Diseases, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China.
  • 5 Department of Neurology, The Second People's Hospital of Shunde, Foshan, 528300, China.
  • 6 JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China.
  • 7 Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
PMID: 38924471 DOI: 10.1002/advs.202404822
Abstract

Small extracellular vesicles (sEVs) contain abundant circular RNAs (circRNAs) and are involved in cellular processes, particularly hypoxia. However, the process that packaging of circRNAs into neuronal sEVs under hypoxia is unclear. This study revealed the spatial mechanism of the Fused in Sarcoma protein (FUS) that facilitates the loading of functional circRNAs into sEVs in hypoxia neurons. It is found that FUS translocated from the nucleus to the cytoplasm and is more enriched in hypoxic neuronal sEVs than in normal sEVs. Cytoplasmic FUS formed aggregates with the sEVs marker protein CD63 in cytoplasmic stress granules (SGs) under hypoxic stress. Meanwhile, cytoplasmic FUS recruited of functional cytoplasmic circRNAs to SGs. Upon relief of hypoxic stress and degradation of SGs, cytoplasmic FUS is transported with those circRNAs from SGs to sEVs. Validation of FUS knockout dramatically reduced the recruitment of circRNAs from SGs and led to low circRNA loading in sEVs, which is also confirmed by the accumulation of circRNAs in the cytoplasm. Furthermore, it is showed that the FUS Zf_RanBP domain regulates the transport of circRNAs to sEVs by interacting with hypoxic circRNAs in SGs. Overall, these findings have revealed a FUS-mediated transport mechanism of hypoxia-related cytoplasmic circRNAs loaded into sEVs under hypoxic conditions.

Keywords

Fused‐in‐Sarcoma protein (FUS); Hypoxia, Small extracellular vesicles (sEVs); Stress granules; circular RNAs (circRNAs).

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