FLASH Interacts with Promyelocytic Leukemia Protein Ⅳ(PML Ⅳ)and Enhances the SUMOylation of p53
10.13865/j.cnki.cjbmb.2024.08.1185
- VernacularTitle:FLASH结合早幼粒细胞白血病蛋白Ⅳ并增强p53的SUMO修饰
- Author:
Meng-Ni WANG
1
;
Zhen-Zhen XIONG
;
Zhi-Ying WANG
;
Jian-Hua WU
;
Xiao-Zhong SHI
Author Information
1. 华南理工大学生物科学与工程学院生物技术系,广州51006
- Keywords:
FADD-like interleukin-1β-converting enzyme associated huge protein(FLASH);
p53;
SU-MOylation;
promyelocytic leukemia protein Ⅳ(PML Ⅳ)
- From:
Chinese Journal of Biochemistry and Molecular Biology
2024;40(10):1426-1440
- CountryChina
- Language:Chinese
-
Abstract:
As a unique gene in the genome,FLASH(FADD-like interleukin-1β-converting enzyme asso-ciated huge protein)/CASP8AP2 is involved in multiple cellular processes,including apoptosis,histone gene pre-mRNA processing,transcriptional regulation,and cell cycle progression.Clinical studies have shown that FLASH is a valuable prognostic marker for acute lymphoblastic leukemia,and a crucial factor for the survival of various cancer cells.Therefore,in-depth research into the function of FLASH may offer new perspectives for the treatment of related diseases.Our previous research identified FLASH as a bind-ing partner of p53,demonstrating that FLASH enhances the transcriptional activity of p53.Here we fur-ther investigate the molecular mechanisms of the interaction between FLASH and p53,revealing that the p53-K386R mutation(SUMOylation residue)attenuated its interaction with FLASH(aa 51-200)and FLASH-SIM(SUMO-interacting motif)(aa 1 534-1 806)significantly.However,SUMO can bind to FLASH-SIM directly,instead of FLASH(aa 51-200).Subsequent research shows that overexpression of FLASH in cells enhances global SUMO1 conjugation and p53-SUMO1 conjugation,therefore providing a plausible explanation for the underlying mechanism of FLASH enhancing the transcriptional activity of p53.Since promyelocytic leukemia protein nuclear body(PML NB)serves as subcellular reactors for SUMO conjugation within the cell,and the PML Ⅳ isoform can specifically enhance the SUMO modifica-tion of p53,we have investigated the interaction between FLASH and PML Ⅳ,and elucidated the struc-tural basis of their interaction:both FLASH-N3A(501-802)and FLASH-C2(1 807-1 981)bind to PML Ⅳ(aa 228-633).Further investigations reveal that they can synergistically enhance global SUMO1 modification as well as SUMO1 modification of p53.The interaction between FLASH and tumor suppres-sors p53 or PML Ⅳ enriches our understanding of its function and reveals the potential mechanism of FLASH in tumor development,therefore offering novel insights into cancer diagnosis and treatment.
