Klc2, the light chain of kinesin-1, is crucial for mediating cargo binding and regulating kinesin-1 motility. Kinesin-1 is a key player in the transport system of cells, moving numerous cellular cargos along the microtubule network in the cytoplasm [3]. This function is essential for normal cellular processes and overall biological function.

In mice, Klc2 deficiency leads to abnormal transport of mitochondria and down-regulation of the GABAA receptor family. Mice lacking Klc2 suffer from low-frequency hearing loss as early as 1 month of age, indicating its importance in cochlear function. Whole-genome sequencing of patients also shows that KLC2 is related to low-frequency hearing in humans. Delivery of adeno-associated virus containing the Klc2 wild-type cDNA sequence to Klc2-null mice results in apparent recovery, including decreased ABR threshold and reduced outer hair cell loss [1]. In zebrafish, knockdown and overexpression of klc2 reveal a mild to severe curly-tail phenotype, suggestive of a neuromuscular disorder [2]. In non-small cell lung cancer (NSCLC), downregulation of KLC2 can promote radiosensitivity by activating the P53 pathway, while HuR-KLC2 forms a positive feedback loop to decrease p53 phosphorylation and weaken radiosensitivity [4].

In summary, Klc2 is essential for normal cellular cargo transport, which is reflected in its impact on cochlear function related to hearing in mice and humans, as well as its role in neuromuscular function in zebrafish and radiosensitivity in NSCLC. The study of Klc2 knockout mouse models has been particularly valuable in uncovering its functions in these specific disease-related biological processes [1,2,4].

References:

1. Fu, Xiaolong, An, Yachun, Wang, Hongyang, Gao, Jiangang, Chai, Renjie. 2021. Deficiency of Klc2 Induces Low-Frequency Sensorineural Hearing Loss in C57BL/6 J Mice and Human. In Molecular neurobiology, 58, 4376-4391. doi:10.1007/s12035-021-02422-w. https://pubmed.ncbi.nlm.nih.gov/34014435/

2. Melo, Uirá S, Macedo-Souza, Lucia I, Figueiredo, Thalita, Zatz, Mayana, Santos, Silvana. 2015. Overexpression of KLC2 due to a homozygous deletion in the non-coding region causes SPOAN syndrome. In Human molecular genetics, 24, 6877-85. doi:10.1093/hmg/ddv388. https://pubmed.ncbi.nlm.nih.gov/26385635/

3. Cockburn, Joseph J B, Hesketh, Sophie J, Mulhair, Peter, O'Connell, Mary J, Way, Michael. 2018. Insights into Kinesin-1 Activation from the Crystal Structure of KLC2 Bound to JIP3. In Structure (London, England : 1993), 26, 1486-1498.e6. doi:10.1016/j.str.2018.07.011. https://pubmed.ncbi.nlm.nih.gov/30197037/

4. Qiao, Simiao, Jiang, Yuhang, Li, Na, Zhu, Xiaoxia. 2023. The kinesin light chain-2, a target of mRNA stabilizing protein HuR, inhibits p53 protein phosphorylation to promote radioresistance in NSCLC. In Thoracic cancer, 14, 1440-1450. doi:10.1111/1759-7714.14886. https://pubmed.ncbi.nlm.nih.gov/37055376/