SPATA2

Current genome-wide association studies of frontotemporal dementia (FTD) are underpowered due to limited samples. Further, common genetic etiologies between FTD and amyotrophic lateral sclerosis (ALS) remain unknown. Using the largest summary statistics of FTD (3526 cases and 9402 controls) and ALS (27,205 cases and 110,881 controls), we found a significant genetic correlation between them (rˆ_g = 0.637, P = 0.032) and identified 190 FTD-related variants within 5 loci (3p22.1, 5q35.1, 9p21.2, 19p13.11, and 20q13.13). Among these, ALS and FTD had causal variants in 9p21.2 and 19p13.11. Moreover, MOBP (3p22.1), C9orf72 (9p21.2), MOB3B (9p21.2), UNC13A (19p13.11), SLC9A8 (20q13.13), SNAI1 (20q13.13), and SPATA2 (20q13.13) were discovered by both SNP- and gene-level analyses, which together discovered 15 FTD-associated genes, with 10 not detected before (IFNK, RNF114, SLC9A8, SPATA2, SNAI1, SCFD1, POLDIP2, TMEM97, G2E3, and PIGW). Functional analyses showed these genes were enriched in heart left ventricle, kidney cortex, and some brain regions. Overall, this study provides insights into genetic determinants of FTD and shared genetic etiology underlying FTD and ALS.

Hypoxic cancer cells resist many anti-neoplastic therapies and can seed recurrence. We found previously that PTP1B deficiency promotes HER2+ breast cancer cell death in hypoxia by activating RNF213, an ∼600kDa protein containing AAA-ATPase domains and two ubiquitin ligase domains (RING and RZ) that also is implicated in Moyamoya disease (MMD), lipotoxicity, and innate immunity. Here we report that PTP1B and ABL1/2 reciprocally control RNF213 phosphorylation on tyrosine-1275. This phosphorylation promotes RNF213 oligomerization and RZ domain activation. The RZ domain ubiquitylates CYLD/SPATA2, and together with the LUBAC complex, induces their degradation. Decreased CYLD/SPATA2 causes NF-κB activation, which together with hypoxia-induced ER-stress triggers GDSMD-dependent pyroptosis. Mutagenesis experiments show that the RING domain negatively regulates the RZ domain. CYLD -deleted HER2+ cell-derived xenografts phenocopy the effects of PTP1B deficiency, and reconstituting RNF213 knockout lines with RNF213 mutants shows that the RZ domain mediates PTP1B-dependent tumor cell death. Our results identify a novel, potentially targetable PTP1B/RNF213/CYCLD/SPATA pathway critical for controlling inflammatory cell death in hypoxic tumors that could be exploited to target hypoxic tumor cells, potentially turning "cold" tumors "hot". Our findings also reveal new insights into RNF213 regulation, and have potentially important implications for the pathogenesis of MMD, atherosclerosis, and inflammatory and auto-immune disorders.

Metastasis is the major cause of cancer-related death of cancer patients. Epithelial-mesenchymal transition (EMT) is one critical process during the cascade of tumor metastasis. EMT is a developmental program exploited by cancer cells to transition from epithelial state to mesenchymal state and confers metastatic properties as well as treatment resistance. Finding factors to inhibit EMT will greatly improve the prognosis patients. Spermatogenesis associated 2 (SPATA2) was originally isolated from human testis and proved playing a role in spermatogenesis. To date, however, the role of SPATA2 in oncogenesis is unknown. In the current study, by mining the public database and validating in a cohort of collected non-small cell lung cancer (NSCLC) specimens, we uncovered that the expression of SPATA2 positively correlated with the prognosis of patients and was an independent prognosis marker in NSCLC. Functional studies proved that ectopic overexpression of SPATA2 inhibited EMT resulting in impaired motility and invasiveness properties in vitro and metastasis in vivo, and increased radiosensitivity in NSCLC. Mechanistic investigation showed that SPATA2 could suppress the β-catenin signaling via attenuating DVL1 ubiquitination to achieve the functions. Taken together, the current study revealed an inhibitory role of SPATA2 on EMT and that SPATA2 could be a potential target for therapy of NSCLC.