bims-pimaco 2024-05-05 papers

Issue of 2024–05–05
two papers selected by
Lucas B. Zeiger

Cell Rep. 2024 May 02. pii: S2211-1247(24)00501-1. [Epub ahead of print]43(5): 114173

Synergistic hyperactivation of both mTORC1 and mTORC2 underlies the neural abnormalities of PTEN-deficient human neurons and cortical organoids.

Navroop K Dhaliwal, Octavia Yifang Weng, Xiaoxue Dong, Afrin Bhattacharya, Mai Ahmed, Haruka Nishimura, Wendy W Y Choi, Aditi Aggarwal, Bryan W Luikart, Qiang Shu, Xuekun Li, Michael D Wilson, Jason Moffat, Lu-Yang Wang, Julien Muffat, Yun Li.

Mutations in the phosphatase and tensin homolog (PTEN) gene are associated with severe neurodevelopmental disorders. Loss of PTEN leads to hyperactivation of the mechanistic target of rapamycin (mTOR), which functions in two distinct protein complexes, mTORC1 and mTORC2. The downstream signaling mechanisms that contribute to PTEN mutant phenotypes are not well delineated. Here, we show that pluripotent stem cell-derived PTEN mutant human neurons, neural precursors, and cortical organoids recapitulate disease-relevant phenotypes, including hypertrophy, electrical hyperactivity, enhanced proliferation, and structural overgrowth. PTEN loss leads to simultaneous hyperactivation of mTORC1 and mTORC2. We dissect the contribution of mTORC1 and mTORC2 by generating double mutants of PTEN and RPTOR or RICTOR, respectively. Our results reveal that the synergistic hyperactivation of both mTORC1 and mTORC2 is essential for the PTEN mutant human neural phenotypes. Together, our findings provide insights into the molecular mechanisms that underlie PTEN-related neural disorders and highlight novel therapeutic targets.

Keywords: CP: Cell biology; CP: Neuroscience; PTEN; autism; brain organoids; epilepsy; mTOR; neurodevelopmental disorders; neurons

DOI: https://doi.org/10.1016/j.celrep.2024.114173

Nat Commun. 2024 May 02. 15(1): 3711

The complete assembly of human LAT1-4F2hc complex provides insights into its regulation, function and localisation.

Di Wu, Renhong Yan, Siyuan Song, Andrew K Swansiger, Yaning Li, James S Prell, Qiang Zhou, Carol V Robinson.

The LAT1-4F2hc complex (SLC7A5-SLC3A2) facilitates uptake of essential amino acids, hormones and drugs. Its dysfunction is associated with many cancers and immune/neurological disorders. Here, we apply native mass spectrometry (MS)-based approaches to provide evidence of super-dimer formation (LAT1-4F2hc)2. When combined with lipidomics, and site-directed mutagenesis, we discover four endogenous phosphatidylethanolamine (PE) molecules at the interface and C-terminus of both LAT1 subunits. We find that interfacial PE binding is regulated by 4F2hc-R183 and is critical for regulation of palmitoylation on neighbouring LAT1-C187. Combining native MS with mass photometry (MP), we reveal that super-dimerization is sensitive to pH, and modulated by complex N-glycans on the 4F2hc subunit. We further validate the dynamic assemblies of LAT1-4F2hc on plasma membrane and in the lysosome. Together our results link PTM and lipid binding with regulation and localisation of the LAT1-4F2hc super-dimer.

DOI: https://doi.org/10.1038/s41467-024-47948-4