title: Loss of lysosome-associated membrane protein 3 (LAMP3) enhances cellular vulnerability against proteasomal inhibition.
abstract: 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.
authors: Experimental Neurology, Department of Neurology, Goethe University Medical School, Frankfurt am Main, Germany.
authors: Jorge Antolio
authors: JA
authors: Dominguez-Bautista
authors: Experimental Neurology, Department of Neurology, Goethe University Medical School, Frankfurt am Main, Germany.
authors: Michael
authors: M
authors: Klinkenberg
authors: Experimental Neurology, Department of Neurology, Goethe University Medical School, Frankfurt am Main, Germany.
authors: Nadine
authors: N
authors: Brehm
authors: Institute of Neurophysiology, Goethe University Medical School, Frankfurt am Main, Germany.
authors: Mahalakshmi
authors: M
authors: Subramaniam
authors: Institute of Neurophysiology, Goethe University Medical School, Frankfurt am Main, Germany.
authors: Beatrice
authors: B
authors: Kern
authors: Institute of Neurophysiology, Goethe University Medical School, Frankfurt am Main, Germany.
authors: Jochen
authors: J
authors: Roeper
authors: Experimental Neurology, Department of Neurology, Goethe University Medical School, Frankfurt am Main, Germany.
authors: Georg
authors: G
authors: Auburger
authors: Experimental Neurology, Department of Neurology, Goethe University Medical School, Frankfurt am Main, Germany. Electronic address: marina.jendrach@charite.de.
authors: Marina
authors: M
authors: Jendrach
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D051907:Lysosomal Membrane Proteins / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059666:Lysosomal-Associated Membrane Protein 3
chemical_list: D051701:Activating Transcription Factor 4; D051907:Lysosomal Membrane Proteins; D009363:Neoplasm Proteins; D046988:Proteasome Endopeptidase Complex; C497109:ATF4 protein, human; C114233:LAMP3 protein, human; D059666:Lysosomal-Associated Membrane Protein 3
keywords: Autophagy; Cancer; LAMP3; Lysosome; Parkinson's disease; Proteasome