The Subcellular Localization of the Uncharacterized Human Disease-Associated Protein Potassium Channel Tetramerization Domain 13 (KCTD13)

KCTD Proteins;KCTD13;Characterization;Localization;Cullin-3;Mitochondria;Mitochondrial Maintenance;not listed

Reyes, Arthur Anthony AHardwick, J. Marie ;

Johns Hopkins University

关键词: KCTD Proteins;    KCTD13;    Characterization;    Localization;    Cullin-3;    Mitochondria;    Mitochondrial Maintenance;    not listed;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/59360/REYES-THESIS-2016.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Human KCTD (potassium (K+) channel tetramerization domain (KCTD) proteins make up a family of 26 largely uncharacterized human proteins containing a single N-terminal BTB/POZ domain most closely related to the T1 domain of potassium channels. KCTDs have been implicated in a variety of human diseases including cancer and neurological disorders. KCTD13 (also known as BACURD1, PDIP1 and POLDIP1), encoded on human chromosome 16p11.2, has been recently implicated in human disease, including neurological disorders and autism spectrum disorder (ASD). However, the molecular mechanisms are unknown. To gain insight on the function of KCTD13, and the family of uncharacterized KCTD proteins, the subcellular localization of expressed KCTD13 was determined, leading to the hypothesis that KCTD13 may have a role in the a protein quality control pathway possibly required for mitochondrial maintenance. Localization of epitope-tagged KCTD13 in mammalian cells was analyzed by immunofluorescence microscopy. Results indicate that KCTD13 forms distinct cytoplasmic structures that co-localize with the E3-ubiquitin ligase Cullin-3 (Cul-3) and mitochondrial organelles. Interestingly, uncoupling of mitochondria by treatment of cells with carbonyl cyanide m-chlorophenyl hydrazone (CCCP) intensifies the co-localization of expressed KCTD13 with the mitochondria and cul-3, suggesting a potential role in the clearance of damaged mitochondrial organelles or components thereof. Further supporting this hypothesis, KCTD13 also co-localizes with autophagy markers LC3, ATG12 and ATG13. KCTD13 also partially localizes with the endosome markers RAB5 and prominently localizes with late endosome marker RAB7. Taken together, these findings are consistent with a potential role of KCTD13 in mitochondrial homeostasis and provide a new perspective in the understanding of molecular mechanisms contributing to ASD and other diseases in which KCTD13 mutations may contribute.