Dataset Information

The BPAN disease protein WDR45 forms condensates with Caprin-1 to regulate stress granule disassembly

ABSTRACT: Beta-propeller protein-associated neurodegeneration (BPAN) is a rare X-linked neurodegenerative disorder primarily caused by mutations in the WD repeat domain 45 (WDR45) gene. While WDR45 has traditionally been linked to autophagy, our study uncovers a previously unrecognized role for WDR45 as a critical regulator of stress granule (SG) disassembly, providing new insights into the pathogenesis of BPAN and related neurodegenerative diseases. We demonstrate that WDR45’s recruitment to SGs via phase separation with Caprin-1 and facilitates SG disassembly by competing with G3BP1 for Caprin-1 binding, thereby modulating the core SG network. BPAN-associated WDR45 mutations, particularly in the WD5 domain, disrupt phase separation properties and impair interaction with Caprin-1, resulting in delayed SG disassembly and correlating with earlier disease onset in BPAN patients. Furthermore, WDR45 depletion exacerbates the accumulation of ALS-associated pathological SGs, highlighting its role in mitigating pathological protein aggregation. Notably, iPSC-derived midbrain neurons from BPAN patients with WDR45 mutation exhibit delayed SG recovery, highlighting the clinical relevance of WDR45 in SG dynamics. These findings reveal a novel function of WDR45 in SG disassembly through its interaction with Caprin-1, providing critical insights into BPAN pathogenesis and identifying potential therapeutic targets for neurodegenerative diseases linked to SG dysregulation.

ORGANISM(S): Homo Sapiens

SUBMITTER: Yang Chen

PROVIDER: PXD062911 | iProX | Mon Apr 14 00:00:00 BST 2025

REPOSITORIES: iProX

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Publications

β-propeller protein-associated neurodegeneration protein WDR45 regulates stress granule disassembly via phase separation with Caprin-1.

Li Yin Y Fang Jie J Ding Yuqi Y Zhang Xilong X Liu Ying Y Qiu Wanting W Xu He H Kang Yunzhe Y Chen Jiayu J Gao Yanyan Y Zhao Yan G YG Yang Peiguo P Wang Bo B Tian Wenmin W Chen Yang Y Bi Wenjian W Zhang Peipei P

Nature communications 20250605 1

β-propeller protein-associated neurodegeneration (BPAN) is a rare X-linked neurodegenerative disorder caused by mutations in the WDR45 gene, yet its molecular mechanisms remain poorly understood. Here, we identify a role for WDR45 in stress granule (SG) disassembly, mediated through its phase separation with Caprin-1. We demonstrate that WDR45 forms gel-like condensates via its WD5 domain, which competitively displaces G3BP1 from Caprin-1 to promote SG disassembly. BPAN-associated WDR45 mutation ...[more]

PMID: 40473629

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Project description:The cellular stress response plays a vital role in regulating homeostasis by modulating cell survival and death. Stress granules (referred to as SGs) are cytoplasmic compartments that allow cells to survive various stressors. Defects in SG assembly and disassembly have been found to play important roles in neurodegenerative diseases, antiviral responses and cancer1–5. Inflammasomes are multi-protein heteromeric complexes that sense intracellular pathogen- and damage-associated molecular patterns and assemble into cytosolic compartments called ASC specks to facilitate caspase-1 (CASP1) activation. This activation of inflammasomes induces secretion of the leaderless proinflammatory cytokines IL-1β and IL-18 and also drives cell fate towards pyroptosis, a form of programmed inflammatory cell death that plays major role in health and disease6–12. Cellular stress sensing can trigger both SGs and inflammasomes; however, they drive contrasting cell fate decisions during stress conditions. Crosstalk between SGs and inflammasomes to decide cell fate has not been well studied. Here we show that the induction of SGs specifically inhibits NLRP3 inflammasome activation, ASC speck formation and pyroptosis. The SG protein DDX3X interacts with NLRP3 to drive inflammasome activation in the absence of SGs. Assembly of SGs leads to the sequestration of DDX3X to inhibit NLRP3 inflammasome function. SGs and the NLRP3 inflammasome compete for DDX3X molecules to coordinate the activation of innate responses and subsequent cell fate decisions under stress conditions. Induction of SGs or loss of DDX3X in the myeloid compartment leads to decreased production of inflammasome-dependent cytokines in vivo. Our findings suggest that macrophages utilize DDX3X availability to interpret stress signals and choose between pro-survival SGs and pyroptotic ASC specks. Together, our data show the role of DDX3X in driving NLRP3 inflammasome and SG assembly, informing a new rheostat-like mechanistic paradigm for regulating live or die cell fate decisions under stress conditions.

Dataset Information

The BPAN disease protein WDR45 forms condensates with Caprin-1 to regulate stress granule disassembly

Publications

β-propeller protein-associated neurodegeneration protein WDR45 regulates stress granule disassembly via phase separation with Caprin-1.

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