bims-lymeca 2023-07-16 papers

Issue of 2023‒07‒16
four papers selected by
Harilaos Filippakis
University of New England

Nat Commun. 2023 Jul 14. 14(1): 3994

Lysosomal cystine export regulates mTORC1 signaling to guide kidney epithelial cell fate specialization.

Marine Berquez, Zhiyong Chen, Beatrice Paola Festa, Patrick Krohn, Svenja Aline Keller, Silvia Parolo, Mikhail Korzinkin, Anna Gaponova, Endre Laczko, Enrico Domenici, Olivier Devuyst, Alessandro Luciani.

Differentiation is critical for cell fate decisions, but the signals involved remain unclear. The kidney proximal tubule (PT) cells reabsorb disulphide-rich proteins through endocytosis, generating cystine via lysosomal proteolysis. Here we report that defective cystine mobilization from lysosomes through cystinosin (CTNS), which is mutated in cystinosis, diverts PT cells towards growth and proliferation, disrupting their functions. Mechanistically, cystine storage stimulates Ragulator-Rag GTPase-dependent recruitment of mechanistic target of rapamycin complex 1 (mTORC1) and its constitutive activation. Re-introduction of CTNS restores nutrient-dependent regulation of mTORC1 in knockout cells, whereas cell-permeant analogues of L-cystine, accumulating within lysosomes, render wild-type cells resistant to nutrient withdrawal. Therapeutic mTORC1 inhibition corrects lysosome and differentiation downstream of cystine storage, and phenotypes in preclinical models of cystinosis. Thus, cystine serves as a lysosomal signal that tailors mTORC1 and metabolism to direct epithelial cell fate decisions. These results identify mechanisms and therapeutic targets for dysregulated homeostasis in cystinosis.

DOI: https://doi.org/10.1038/s41467-023-39261-3

FEBS J. 2023 Jul 11.

Lysosome pH-regulated H+ /K+ switching channel involved in maintaining lysosomal homeostasis.

Yizhen Wang, Wei Li, Qiaochu Wang.

Lysosomal pH setpoint and H+ homeostasis is key to the lysosome's functions. The Parkinson's disease-risk protein TMEM175, originally identified as lysosomal K+ channel, works as a H+ -activated H+ channel and discharges the lysosomal H+ store when it is hyper-acidified. Yang et al. indicate that TMEM175 is permeable for both K+ and H+ in the same pore and charges the lysosome with H+ under certain conditions. The charge and discharge functions are under regulation of the lysosomal matrix and glycocalyx layer. Their presented work indicates that TMEM175 performs as a multi-functional channel regulating lysosomal pH in response to physiological conditions.

Keywords: TMEM175; glycocalyx; lysosome H+ fluxes

DOI: https://doi.org/10.1111/febs.16895

JCI Insight. 2023 07 10. pii: e158098. [Epub ahead of print]8(13):

Inhibition of phosphodiesterase 4D suppresses mTORC1 signaling and pancreatic cancer growth.

Mi-Hyeon Jeong, Greg Urquhart, Cheryl Lewis, Zhikai Chi, Jenna L Jewell.

The mammalian target of rapamycin complex 1 (mTORC1) senses multiple upstream stimuli to orchestrate anabolic and catabolic events that regulate cell growth and metabolism. Hyperactivation of mTORC1 signaling is observed in multiple human diseases; thus, pathways that suppress mTORC1 signaling may help to identify new therapeutic targets. Here, we report that phosphodiesterase 4D (PDE4D) promotes pancreatic cancer tumor growth by increasing mTORC1 signaling. GPCRs paired to Gαs proteins activate adenylyl cyclase, which in turn elevates levels of 3',5'-cyclic adenosine monophosphate (cAMP), whereas PDEs catalyze the hydrolysis of cAMP to 5'-AMP. PDE4D forms a complex with mTORC1 and is required for mTORC1 lysosomal localization and activation. Inhibition of PDE4D and the elevation of cAMP levels block mTORC1 signaling via Raptor phosphorylation. Moreover, pancreatic cancer exhibits an upregulation of PDE4D expression, and high PDE4D levels predict the poor overall survival of patients with pancreatic cancer. Importantly, FDA-approved PDE4 inhibitors repress pancreatic cancer cell tumor growth in vivo by suppressing mTORC1 signaling. Our results identify PDE4D as an important activator of mTORC1 and suggest that targeting PDE4 with FDA-approved inhibitors may be beneficial for the treatment of human diseases with hyperactivated mTORC1 signaling.

Keywords: Cancer; Cell Biology

DOI: https://doi.org/10.1172/jci.insight.158098

bioRxiv. 2023 Jun 26. pii: 2023.06.25.546311. [Epub ahead of print]

Lysosomal mitochondrial interaction promotes tumor growth in squamous cell carcinoma of the head and neck.

Avani Gopalkrishnan, Nathaniel Wang, Silvia Cruz-Rangel, Abdul Yassin- Kassab, Sruti Shiva, Chareeni Kurukulasuriya, Satdarshan P Monga, Ralph J DeBerardinis, Kirill Kiselyov, Umamaheswar Duvvuri.

Tumor growth and proliferation are regulated by numerous mechanisms. Communication between intracellular organelles has recently been shown to regulate cellular proliferation and fitness. The way lysosomes and mitochondria communicate with each other (lysosomal/mitochondrial interaction) is emerging as a major determinant of tumor proliferation and growth. About 30% of squamous carcinomas (including squamous cell carcinoma of the head and neck, SCCHN) overexpress TMEM16A, a calcium-activated chloride channel, which promotes cellular growth and negatively correlates with patient survival. TMEM16A has recently been shown to drive lysosomal biogenesis, but its impact on mitochondrial function is unclear. Here, we show that (1) patients with high TMEM16A SCCHN display increased mitochondrial content specifically complex I; (2) In vitro and in vivo models uniquely depend on mitochondrial complex I activity for growth and survival; (3) β-catenin/NRF2 signaling is a critical linchpin that drives mitochondrial biogenesis, and (4) mitochondrial complex I and lysosomal function are codependent for proliferation. Taken together, our data demonstrate that LMI drives tumor proliferation and facilitates a functional interaction between lysosomes and mitochondria. Therefore, inhibition of LMI may serve as a therapeutic strategy for patients with SCCHN.

DOI: https://doi.org/10.1101/2023.06.25.546311