Huang Yonghong, Zhou Feng, Xu Xin, Wang Yaqun, Quintero Michaela, Liu Siyang, Liu Cong, Zhu Guangxun, Cai Yafei, Dong Zheng, Bollag Roni, Wu Guangyu, Sabbatini Maria Eugenia, Li Honglin
Department of Pathophysiology, Jiangxi Provincial Key Laboratory of Tumor Biology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, People's Republic of China.
Department of Biochemistry and Molecular Biology, Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, Georgia, United States.
Am J Physiol Cell Physiol. 2025 Aug 1;329(2):C513-C529. doi: 10.1152/ajpcell.00284.2025. Epub 2025 Jul 10.
The acinus is the functional unit of the exocrine pancreas that produces and secretes a large quantity of digestive enzymes. Damage and dysfunction of pancreatic acinar cells (PACs) may lead to malnutrition, pancreatitis, and other pathological conditions. CDK5 regulatory subunit-associated protein 3 (Cdk5rap3), a multifunctional protein, is essential for animal development and normal physiology of multiple organs and tissues. Interestingly, the recent studies suggest its involvement in endoplasmic reticulum (ER)-phagy, a lysosomal degradation of the subdomains of the endoplasmic reticulum (ER). Herein, we attempted to investigate its physiological function in pancreatic acinar cells. We found that -deficient PACs contained fewer zymogen granules and underwent acinar-to-ductal metaplasia (ADM) and apoptosis, thereby resulting in a significant loss of acinar compartment. Interestingly, ablation led to the increase of lysosomal hydrolase cathepsin B and lysosome-associated membrane protein 1 (LAMP1), indicating its novel function in the regulation of lysosomal homeostasis and activity. Elevated cathepsin B activity may lead to aberrant activation of trypsinogen and apoptosis of -deficient acinar cells, whereas the increase of lysosomal proteins may enhance lysosomal activity that in turn promotes ADM. Furthermore, knockout led to substantial changes in the rough ER structure and a significant increase in selective ER membrane proteins, including cytoskeleton-linking membrane protein 63 (CLIMP63). Our results from both mouse tissues and tissue culture cells strongly suggest that Cdk5rap3 plays a pivotal role in regulating homeostasis of the lysosome and the ER that is essential for the survival and physiological function of pancreatic acinar cells. Our current study has demonstrated a critical role of Cdk5rap3 protein in the maintenance and function of pancreatic acinar cells. Cdk5rap3 functions as a key regulator of the homeostasis of subcellular organelles, such as the lysosome and the ER, and its deficiency leads to loss of pancreatic mass and may contribute to the pathogenesis of pancreatic diseases.
腺泡是外分泌胰腺的功能单位，可产生和分泌大量消化酶。胰腺腺泡细胞（PACs）的损伤和功能障碍可能导致营养不良、胰腺炎及其他病理状况。细胞周期蛋白依赖性激酶5调节亚基相关蛋白3（Cdk5rap3）是一种多功能蛋白，对动物发育及多个器官和组织的正常生理功能至关重要。有趣的是，最近的研究表明它参与内质网自噬，即内质网（ER）亚结构域的溶酶体降解。在此，我们试图研究其在胰腺腺泡细胞中的生理功能。我们发现，Cdk5rap3缺陷的PACs含有的酶原颗粒较少，并经历了腺泡-导管化生（ADM）和凋亡，从而导致腺泡区显著丧失。有趣的是，Cdk5rap3缺失导致溶酶体水解酶组织蛋白酶B和溶酶体相关膜蛋白1（LAMP1）增加，表明其在调节溶酶体稳态和活性方面具有新功能。组织蛋白酶B活性升高可能导致胰蛋白酶原异常激活和Cdk5rap3缺陷腺泡细胞凋亡，而溶酶体蛋白增加可能增强溶酶体活性，进而促进ADM。此外，Cdk5rap3敲除导致粗面内质网结构发生实质性变化，包括细胞骨架连接膜蛋白63（CLIMP6）在内的选择性内质网膜蛋白显著增加。我们在小鼠组织和组织培养细胞中的研究结果均强烈表明，Cdk5rap3在调节溶酶体和内质网稳态中起关键作用，而这对胰腺腺泡细胞的存活和生理功能至关重要。我们目前的研究证明了Cdk5rap3蛋白在胰腺腺泡细胞的维持和功能中的关键作用。Cdk5rap3作为溶酶体和内质网等亚细胞器稳态的关键调节因子，其缺乏会导致胰腺质量丧失，并可能促成胰腺疾病的发病机制。
