Journal
FEBS JOURNAL
Volume 284, Issue 1, Pages 56-76Publisher
WILEY-BLACKWELL
DOI: 10.1111/febs.13949
Keywords
ALG-2; Ca2+-binding protein; endoplasmic reticulum exit sites; protein-protein interaction; Trk-fused gene (TFG) protein
Categories
Funding
- World Premier International Research Center Initiative (WPI), Japan
- [15K07384]
- [14J09452]
- [26292050]
- [15K18680]
- [JP15H05955]
- Grants-in-Aid for Scientific Research [26292050, 15K18680, 14J09452, 15K07384] Funding Source: KAKEN
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Apoptosis-linked gene 2 (ALG-2), which is a gene product of PDCD6, is a 22-kDa Ca2+-binding protein. Accumulating evidence points to a role for ALG-2 as a Ca2+-responsive adaptor protein. On binding to Ca2+, ALG2 undergoes a conformational change that facilitates its interaction with various proteins. It also forms a homodimer and heterodimer with peflin, a paralog of ALG-2. However, the differences in cellular roles for the ALG2 homodimer and ALG-2/peflin heterodimer are unclear. In the present study, we found that Trk-fused gene (TFG) protein interacted with the ALG-2 homodimer. Immunostaining analysis revealed that TFG and ALG-2 partially overlapped at endoplasmic reticulum exit sites (ERES), a platform for COPII-mediated protein transport from the endoplasmic reticulum. Time-lapse live-cell imaging demonstrated that both green fluorescent protein-fused TFG and mCherry-fused ALG-2 are recruited to ERES after thapsigargin treatment, which raises intracellular Ca2+ levels. Furthermore, overexpression of ALG-2 induced the accumulation of TFG at ERES. TFG has an ALG-2-binding motif and deletion of the motif decreased TFG binding to ALG-2 and shortened its half-life at ERES, suggesting a critical role for ALG-2 in retaining TFG at ERES. We also demonstrated, by in vitro cross-linking assays, that ALG-2 promoted the polymerization of TFG in a Ca2+-dependent manner. Collectively, the results suggest that ALG-2 acts as a Ca2+-sensitive adaptor to concentrate and polymerize TFG at ERES, supporting a potential role for ALG-2 in COPII-dependent trafficking from the endoplasmic reticulum.
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