Dominguez-Bautista Jorge Antolio, Klinkenberg Michael, Brehm Nadine, Subramaniam Mahalakshmi, Kern Beatrice, Roeper Jochen, Auburger Georg, Jendrach Marina
Experimental Neurology, Department of Neurology, Goethe University Medical School, Frankfurt am Main, Germany.
Institute of Neurophysiology, Goethe University Medical School, Frankfurt am Main, Germany.
Eur J Cell Biol. 2015 Mar-Apr;94(3-4):148-61. doi: 10.1016/j.ejcb.2015.01.003. Epub 2015 Jan 30.
The family of lysosome-associated membrane proteins (LAMP) includes the ubiquitously expressed LAMP1 and LAMP2, which account for half of the proteins in the lysosomal membrane. Another member of the LAMP family is LAMP3, which is expressed only in certain cell types and differentiation stages. LAMP3 expression is linked with poor prognosis of certain cancers, and the locus where it is encoded was identified as a risk factor for Parkinson's disease (PD). Here, we investigated the role of LAMP3 in the two main cellular degradation pathways, the proteasome and autophagy. LAMP3 mRNA was not detected in mouse models of PD or in the brain of human patients. However, it was strongly induced upon proteasomal inhibition in the neuroblastoma cell line SH-SY5Y. Induction of LAMP3 mRNA following proteasomal inhibition was dependent on UPR transcription factor ATF4 signaling and induced autophagic flux. Prevention of LAMP3 induction enhanced apoptotic cell death. In summary, these data demonstrate that LAMP3 regulation as part of the UPR contributes to protein degradation and cell survival during proteasomal dysfunction. This link between autophagy and the proteasome may be of special importance for the treatment of tumor cells with proteasomal inhibitors.
溶酶体相关膜蛋白(LAMP)家族包括普遍表达的LAMP1和LAMP2,它们占溶酶体膜中蛋白质的一半。LAMP家族的另一个成员是LAMP3,它仅在某些细胞类型和分化阶段表达。LAMP3的表达与某些癌症的不良预后相关,其编码位点被确定为帕金森病(PD)的一个风险因素。在此,我们研究了LAMP3在两种主要细胞降解途径即蛋白酶体和自噬中的作用。在PD小鼠模型或人类患者大脑中未检测到LAMP3 mRNA。然而,在神经母细胞瘤细胞系SH-SY5Y中,蛋白酶体抑制后LAMP3被强烈诱导。蛋白酶体抑制后LAMP3 mRNA的诱导依赖于未折叠蛋白反应(UPR)转录因子ATF4信号传导并诱导自噬通量。阻止LAMP3的诱导会增强凋亡细胞死亡。总之,这些数据表明,作为UPR一部分的LAMP3调节在蛋白酶体功能障碍期间有助于蛋白质降解和细胞存活。自噬与蛋白酶体之间的这种联系对于用蛋白酶体抑制剂治疗肿瘤细胞可能具有特别重要的意义。