C12ORF54介导脂滴向溶酶体的递送，其突变导致儿童期起病的代谢功能障碍相关脂肪性肝病
C12ORF54 mediates lipid droplet delivery to lysosomes with mutation causing childhood-onset metabolic dysfunction-associated steatotic liver disease.
摘要(中文译文)
细胞脂滴（LD）周转对肝脏代谢稳态至关重要，而脂滴清除障碍与脂肪性肝病的关联日益受到重视。我们描述了一种此前未被认识的脂滴周转机制以及由其破坏所致的人类疾病。一名患有代谢功能障碍相关脂肪性肝病（MASLD）的2岁男孩经外显子测序被发现携带超罕见纯合C12ORF54错义变异（c.134A>G；p.Q45R）。我们发现野生型C12ORF54是一种保守蛋白，通过中央两亲性螺旋结合脂滴，并通过N端螺旋与BORC亚基KXD1相互作用锚定于溶酶体，从而实现脂滴直接沉积进入溶酶体。p.Q45R替换在空间上破坏了两亲性螺旋的稳定性，消除了KXD1结合，阻止了脂滴和溶酶体靶向并阻断了脂滴沉积。先证者细胞中脂滴和酰基脂质种类蓄积，因过量活性氧（ROS）导致脂毒性应激，并表现出细胞周期阻滞和细胞死亡。本研究提示直接溶酶体脂滴沉积缺陷是儿童期起病的MASLD样肝脏表型的原因，并发现C12ORF54-KXD1相互作用轴可能是肝脏脂滴稳态的潜在贡献因素。
Abstract
Cellular lipid droplet (LD) turnover is essential for metabolic homeostasis in liver, and failures in LD clearance are increasingly linked to fatty liver disease. We describe a previously unrecognized mechanism of LD turnover and a human disorder caused by its disruption. A 2-year-old boy with metabolic dysfunction-associated steatotic liver disease (MASLD) was found by exome sequencing to carry an ultrarare homozygous C12ORF54 missense variant (c.134A>G; p.Q45R). We find that wild-type C12ORF54 is a conserved protein that binds LDs via a central amphipathic helix and tethers to lysosomes through an N-terminal helix interaction with the BORC subunit KXD1, enabling direct deposition of LDs into lysosomes. The p.Q45R substitution sterically destabilizes the amphipathic helix, abolishes KXD1 binding, prevents LD and lysosome targeting and blocks LD deposition. Proband cells accumulate LDs and acyl lipid species, lipotoxic stress due to excess ROS, and exhibit cell-cycle arrest and cell death. This study implicates defective direct lysosomal LD deposition as a cause of childhood-onset MASLD-like hepatic phenotype, and finds the C12ORF54-KXD1 interaction axis as a potential contributor to LD homeostasis in liver.
如何引用
AMA
Ashish Negi, Abhishek Kumar, Yogendra Pratap Mathuria, Shailesh Kumar Gupta, Debasish Kumar Ghosh. C12ORF54 mediates lipid droplet delivery to lysosomes with mutation causing childhood-onset metabolic dysfunction-associated steatotic liver disease.. Biochimica et biophysica acta. Molecular basis of disease. 2027; doi:10.1016/j.bbadis.2026.168453.
APA
Ashish Negi, Abhishek Kumar, Yogendra Pratap Mathuria, Shailesh Kumar Gupta, Debasish Kumar Ghosh (2027). C12ORF54 mediates lipid droplet delivery to lysosomes with mutation causing childhood-onset metabolic dysfunction-associated steatotic liver disease.. Biochimica et biophysica acta. Molecular basis of disease. https://doi.org/10.1016/j.bbadis.2026.168453
GB/T 7714
Ashish Negi, Abhishek Kumar, Yogendra Pratap Mathuria, Shailesh Kumar Gupta, Debasish Kumar Ghosh. C12ORF54 mediates lipid droplet delivery to lysosomes with mutation causing childhood-onset metabolic dysfunction-associated steatotic liver disease.[J]. Biochimica et biophysica acta. Molecular basis of disease, 2027 doi:10.1016/j.bbadis.2026.168453.
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