RRC ID 65405
Author Inukai R, Mori K, Kuwata K, Suzuki C, Maki M, Takahara T, Shibata H.
Title The Novel ALG-2 Target Protein CDIP1 Promotes Cell Death by Interacting with ESCRT-I and VAPA/B.
Journal Int J Mol Sci
Abstract Apoptosis-linked gene 2 (ALG-2, also known as PDCD6) is a member of the penta-EF-hand (PEF) family of Ca2+-binding proteins. The murine gene encoding ALG-2 was originally reported to be an essential gene for apoptosis. However, the role of ALG-2 in cell death pathways has remained elusive. In the present study, we found that cell death-inducing p53 target protein 1 (CDIP1), a pro-apoptotic protein, interacts with ALG-2 in a Ca2+-dependent manner. Co-immunoprecipitation analysis of GFP-fused CDIP1 (GFP-CDIP1) revealed that GFP-CDIP1 associates with tumor susceptibility gene 101 (TSG101), a known target of ALG-2 and a subunit of endosomal sorting complex required for transport-I (ESCRT-I). ESCRT-I is a heterotetrameric complex composed of TSG101, VPS28, VPS37 and MVB12/UBAP1. Of diverse ESCRT-I species originating from four VPS37 isoforms (A, B, C, and D), CDIP1 preferentially associates with ESCRT-I containing VPS37B or VPS37C in part through the adaptor function of ALG-2. Overexpression of GFP-CDIP1 in HEK293 cells caused caspase-3/7-mediated cell death. In addition, the cell death was enhanced by co-expression of ALG-2 and ESCRT-I, indicating that ALG-2 likely promotes CDIP1-induced cell death by promoting the association between CDIP1 and ESCRT-I. We also found that CDIP1 binds to vesicle-associated membrane protein-associated protein (VAP)A and VAPB through the two phenylalanines in an acidic tract (FFAT)-like motif in the C-terminal region of CDIP1, mutations of which resulted in reduction of CDIP1-induced cell death. Therefore, our findings suggest that different expression levels of ALG-2, ESCRT-I subunits, VAPA and VAPB may have an impact on sensitivity of anticancer drugs associated with CDIP1 expression.
Volume 22(3)
Published 2021-1-25
DOI 10.3390/ijms22031175
PII ijms22031175
PMID 33503978
PMC PMC7865452
MeSH Amino Acid Motifs Amino Acid Sequence Apoptosis Regulatory Proteins / genetics Apoptosis Regulatory Proteins / metabolism* Binding Sites Calcium / metabolism Calcium-Binding Proteins / genetics Calcium-Binding Proteins / metabolism* Cell Death / genetics Cell Line Endosomal Sorting Complexes Required for Transport / metabolism* Humans Protein Binding Structure-Activity Relationship Vesicular Transport Proteins / metabolism*
IF 4.556
DNA material Genome Network Project Human cDNA Clone IRAL009L17 (HGY083881) IRAL008O12 (HGY083548)