LAMP3 inhibits autophagy and contributes to cell death by lysosomal membrane permeabilization

Sjögren syndrome (SS) is a chronic and progressive autoimmune disease characterized by dry mouth and dry eyes, and characteristic autoantibodies. Evidence of altered macroautophagy/autophagy and apoptosis has been associated with SS, but a mechanistic understanding of the gene expression changes associated with these abnormal processes has not been realized. Recently, increased LAMP3 (lysosomal associated membrane protein 3) expression was found in a subset of SS patients and was associated with increased apoptosis and autoantigen accumulation and release. To better understand how LAMP3 expression might modulate apoptosis, cell biology, and biochemical studies were used to examine the effect of LAMP3 expression in minor salivary gland cells. LAMP3 expression resulted in degradation of LAMP1 increasing lysosomal membrane permeabilization and relocalization of cathepsins to the cytoplasm, resulting in destabilizing autophagic flux and caspase activation. These findings highlight the central role of LAMP3 expression in the pathogenesis of SS.

干燥综合征（Sjögren syndrome, SS）是一种慢性进行性自身免疫性疾病，以口干燥症、眼干燥症及特征性自身抗体为典型临床与实验室特征。现有研究证实巨自噬（macroautophagy）/自噬（autophagy）与细胞凋亡（apoptosis）发生异常的现象与干燥综合征密切相关，但目前尚未明确这些异常病理过程背后的基因表达改变的具体调控机制。近期研究发现，部分干燥综合征患者体内存在溶酶体相关膜蛋白3（lysosomal associated membrane protein 3, LAMP3）的表达上调，且该现象与细胞凋亡加剧、自身抗原积累及释放增加显著相关。为深入探究溶酶体相关膜蛋白3的表达如何调控细胞凋亡、细胞生物学进程与生化反应，研究人员通过细胞生物学与生物化学实验，检测了溶酶体相关膜蛋白3在小唾液腺细胞中的表达效应。实验结果显示，溶酶体相关膜蛋白3的表达可导致溶酶体相关膜蛋白1（LAMP1）降解，提升溶酶体膜通透性，并使组织蛋白酶（cathepsins）重新定位至细胞质，进而破坏自噬流（autophagic flux）的稳定性并激活半胱天冬酶（caspase）。上述研究结果凸显了溶酶体相关膜蛋白3的表达在干燥综合征发病机制中的核心作用。