Data from TSC2 Interacts with HDLBP/Vigilin and Regulates Stress Granule Formation

Abstract

<div>Abstract<p>Tuberous sclerosis complex (TSC) is caused by mutations of either the <i>TSC1</i> or <i>TSC2</i> tumor suppressor gene. TSC causes tumors of the brain, heart, kidney, skin and lymphangioleiomyomatosis (LAM). Here we report that the TSC2 protein physically binds to high-density lipoprotein binding protein (HDLBP), also called vigilin, a core stress granule (SG) protein, and that TSC2 localizes to SGs. SGs contain mRNAs and translation initiation complexes, and regulate gene expression by sequestering specific transcripts, thereby serving a cytoprotective role. TSC2 has never before been shown to localize to SGs and knocking down vigilin impacts SG translocation of TSC2. TSC2-deficient cells showed a striking increase in the number of SGs after thermal shock and arsenite treatment relative to Tsc2-expressing cells. Our findings also show that murine kidney lysates from a model of TSC have increased levels of SG components including G3BP1 and Caprin1. G3BP1 and Caprin are elevated in renal angiomyolipomas (a renal tumor common in patients with TSC) compared with control normal kidney. G3BP1 is also elevated in TSC-associated subependymal giant cell astrocytomas. We found that genetic inhibition of G3BP1 inhibits the proliferation of TSC2-deficient cells <i>in vitro</i>. Finally, in a mouse model of TSC, genetic inhibition of SGs suppresses cell growth, suggesting that targeting SGs may have efficacy in the therapy of TSC.</p>Implications:<p>This study demonstrates that TSC2 physically interacts with HDLBP/vigilin, a component of SGs, that TSC2 localizes to SG and that TSC2-deficient cells have more SGs, suggesting that SGs represent a novel therapeutic target in TSC.</p></div>

Unravelling novel functions of the MTOR network across subcellular compartments

“…Likewise, the S. cerevisiae RPTOR orthologue KOG1 and TOR1 localize to SGs (Takahara and Maeda, 2012). Also the TSC subunit TSC2 (Kosmas et al, 2021) and the mTORC1 substrates S6K1 and 2 (Sfakianos et al, 2018) have been recently reported at SGs (Figure 2), which might impinge on mTORC1 activity as well. It will be interesting to delineate the coordination of the recruitment and disassembly of the TSC and mTORC1 complexes and their substrates at SGs.…”

“…In contrast, mTORC1 inhibition has been shown by several studies to reduce SG formation upon heat shock, arsenite, and the proteasome inhibitor Bortezomib (Fournier et al, 2013;Mazan-Mamczarz et al, 2015;Sfakianos et al, 2018;Heberle et al, 2019). Conversely, TSC2 deficiency, known to hyperactivate mTORC1, increases the number of SGs formed upon arsenite or heat stress (Kosmas et al, 2021). As discussed above, mTORC1 activity under stress is enhancedat least in partby PI3Ks and MAPK14 (Heberle et al, 2019).…”