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UFMylation orchestrates kidney development through YAP stabilization
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DOI：10.1016/j.jbc.2026.113285.png)
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Abstract
En 中文
The ubiquitin-like modifier UFM1 regulates diverse cellular processes through UFMylation. We previously demonstrated that UFMylation ligase UFL1 deficiency induces endoplasmic reticulum stress and culminates in kidney atrophy in adult mice, yet the critical UFMylation substrates and its function in organogenesis remains largely unexplored. Here, we report UFMylation is required for mammalian kidney development through Yes-associated protein (YAP) stabilization. Genetic ablation of Ufl1 in the murine kidney results in severe dysplasia, phenocopying the loss of YAP activity. We identified YAP as a substrate for UFMylation at lysine 76 (K76), which shields YAP from ubiquitin-proteasome degradation, thereby promoting its nuclear accumulation and transcriptional activation. Additionally, we discovered UFSP1, rather than UFSP2, acted as the primary protease for YAP de-UFMylation, whose depletion promoted YAP stabilization and activation. These findings establish UFMylation as a crucial post-translational mechanism licensing YAP-dependent transcription during development, reveal unexpected complexity in the regulation of YAP UFMylation, and implicate a previously unrecognized etiological pathway for kidney dysplasia.
Keywords:
UFMylation
UFL1
YAP
kidney dysplasia
UFSP1
UFSP2
ARPC4
actin-related proteins 4
ASC1
activating signal cointegrator 1
CHX
cycloheximide
CKO
conditional knockout
CK1δ/ɛ
casein kinase 1δ/ɛ
CYB5R3
NADH-cytochrome b5 reductase 3
E14
embryonic day 14
HESCs
human embryonic pluripotent stem cells
K76
lysine 76
LATS1/2
large tumour suppressor kinase 1/2
MOB1
MOB kinase activator 1
MRE11
meiotic recombination 11
MST1/2
mammalian STE20-like kinase 1/2
PD-L1
programmed death ligand-1
P0
postnatal day 0
RIG-1
retinoic acid-inducible gene 1
RPL26
ribosomal protein L26
S127
serine 127
WT
wild-type
YAP
Yes-associated protein
Journal
IF:
3.9
Papers:
11.2W
Citations:
28.3W
Organization
Cited Papers