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Abstract
Previously we reported that the expression of promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARα) fusion gene, which is caused by specific translocation (15;17) in acute promyelocytic leukemia, can enhance constitutive autophagic activity in leukemic and nonleukemic cells, and PML overexpression can sequestrate part of microtubule-associated protein light chain 3 (LC3) protein in PML nuclear bodies, suggesting that LC3 protein also distributes into nuclei although it is currently thought to function primarily in the cytoplasm, the site of autophagosomal formation. However, its potential significance of nucleoplasmic localizations remains greatly elusive. Here we demonstrate that PML interacts with LC3 in a cell type-independent manner as assessed by Co-IP assay and co-localization observation. Overexpressed PML significantly coprecipitates with endogenous and nuclear LC3 protein. Furthermore, a fraction of endogenous PML protein is found to be co-localized with LC3 protein under steady state condition, which is further enhanced by IFNα induction, indicating that PML up-regulation potentiates this interaction. Additionally, DsRed-PML associates with EGFP-LC3 during telophase and G1 phase but not in metaphase and anaphase. Two potential LC3-interacting region (LIR) motifs in PML are required for interaction of PML with LC3 while this association is independent of autophagic activity. Finally, we show that interaction between PML and LC3 contributes to cell growth inhibition function of PML. Considering that PML is an important tumor suppressor, we propose that nuclear portion of LC3 protein may associate with PML to control cell growth for prevention and inhibition of cancer occurrence and development.
Highlights
Promyelocytic leukemia (PML) gene was discovered as a fusion partner of human retinoic acid receptor alpha (RARa) gene, resulting in PML-RARa fusion protein that is critical for pathogenesis of acute promyelocytic leukemia (APL) [1, 2, 3]
The results showed that anti-Flag antibody could effectively pull down Flag-PML I/IV proteins from whole cell lysates (WCL), cytosol and nuclei fractions, together with endogenous and light chain 3 (LC3)-II proteins derived from WCL and nuclei but not cytosol (Figure 1d), suggesting PML interacted with endogenous and nuclear LC3 proteins
One previous report that LC3-II is found in nuclei of fresh rat hepatocytes by biochemical fractionation approach supports the notion that nuclear LC3 is mainly LC3-II form [39]
Summary
Promyelocytic leukemia (PML) gene was discovered as a fusion partner of human retinoic acid receptor alpha (RARa) gene, resulting in PML-RARa fusion protein that is critical for pathogenesis of acute promyelocytic leukemia (APL) [1, 2, 3]. PML protein is characterized by presence of RBCC or tripartite motif (TRIM), which consists of a C3HC4 zinc-finger motif (RING finger), two cysteine-rich and zinc-binding regions (B-boxes), followed by leucine coiled-coil region [4]. Primary and single PML gene transcript undergoes extensive alternative splicing, resulting in expression of seven isoforms designated PML I to PML VIIb. Primary and single PML gene transcript undergoes extensive alternative splicing, resulting in expression of seven isoforms designated PML I to PML VIIb They share the same N-terminal region containing RBCC/TRIM but differ in their C-terminal sequences. PML NBs are disrupted and dispersed in microspeckles in the leukemic blasts of APL patients [10, 11], suggesting loss of PML NBs’ integrity contributes to leukemogenesis
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