bims-raghud 2024-12-01 papers

Issue of 2024–12–01
five papers selected by
Irene Sambri, TIGEM

Nat Commun. 2024 Nov 23. 15(1): 10163

The nutrient-sensing Rag-GTPase complex in B cells controls humoral immunity via TFEB/TFE3-dependent mitochondrial fitness.

Xingxing Zhu, Yue Wu, Yanfeng Li, Xian Zhou, Jens O Watzlawik, Yin Maggie Chen, Ariel L Raybuck, Daniel D Billadeau, Virginia Smith Shapiro, Wolfdieter Springer, Jie Sun, Mark R Boothby, Hu Zeng.

Germinal center (GC) formation, which is an integrant part of humoral immunity, involves energy-consuming metabolic reprogramming. Rag-GTPases are known to signal amino acid availability to cellular pathways that regulate nutrient distribution such as the mechanistic target of rapamycin complex 1 (mTORC1) pathway and the transcription factors TFEB and TFE3. However, the contribution of these factors to humoral immunity remains undefined. Here, we show that B cell-intrinsic Rag-GTPases are critical for the development and activation of B cells. RagA/RagB deficient B cells fail to form GCs, produce antibodies, and to generate plasmablasts during both T-dependent (TD) and T-independent (TI) humoral immune responses. Deletion of RagA/RagB in GC B cells leads to abnormal dark zone (DZ) to light zone (LZ) ratio and reduced affinity maturation. Mechanistically, the Rag-GTPase complex constrains TFEB/TFE3 activity to prevent mitophagy dysregulation and maintain mitochondrial fitness in B cells, which are independent of canonical mTORC1 activation. TFEB/TFE3 deletion restores B cell development, GC formation in Peyer's patches and TI humoral immunity, but not TD humoral immunity in the absence of Rag-GTPases. Collectively, our data establish the Rag GTPase-TFEB/TFE3 pathway as a likely mTORC1 independent mechanism to coordinating nutrient sensing and mitochondrial metabolism in B cells.

DOI: https://doi.org/10.1038/s41467-024-54344-5

bioRxiv. 2024 Nov 15. pii: 2024.11.15.623810. [Epub ahead of print]

Structural basis for growth factor and nutrient signal integration on the lysosomal membrane by mTORC1.

Zhicheng Cui, Alessandra Esposito, Gennaro Napolitano, Andrea Ballabio, James H Hurley.

Mechanistic target of rapamycin complex 1 (mTORC1), which consists of mTOR, Raptor, and mLST8, receives signaling inputs from growth factor signals and nutrients. These signals are mediated by the Rheb and Rag small GTPases, respectively, which activate mTORC1 on the cytosolic face of the lysosome membrane. We biochemically reconstituted the activation of mTORC1 on membranes by physiological submicromolar concentrations of Rheb, Rags, and Ragulator. We determined the cryo-EM structure and found that Raptor and mTOR directly interact with the membrane at anchor points separated by up to 230 Å across the membrane surface. Full engagement of the membrane anchors is required for maximal activation, which is brought about by alignment of the catalytic residues in the mTOR kinase active site. The observations show at the molecular and atomic scale how converging signals from growth factors and nutrients drive mTORC1 recruitment to and activation on the lysosomal membrane in a three-step process, consisting of (1) Rag-Ragulator-driven recruitment to within ∼100 Å of the lysosomal membrane, (2) Rheb-driven recruitment to within ∼40 Å, and finally (3) direct engagement of mTOR and Raptor with the membrane. The combination of Rheb and membrane engagement leads to full catalytic activation, providing a structural explanation for growth factor and nutrient signal integration at the lysosome.

DOI: https://doi.org/10.1101/2024.11.15.623810

bioRxiv. 2024 Nov 22. pii: 2024.11.21.624702. [Epub ahead of print]

SFPQ-TFE3 gene fusion reciprocally regulates mTORC1 activity and induces lineage plasticity in a novel mouse model of renal tumorigenesis.

Kaushal Asrani, Adrianna Amaral, Juhyung Woo, Sanaz Nourmohammadi Abadchi, Thiago Vidotto, Kewen Feng, Hans B Liu, Mithila Kasbe, Masaya Baba, Yuichi Oike, Patricia Outeda, Terry Watnick, Avi Z Rosenberg, Laura S Schmidt, W Marston Linehan, Pedram Argani, Tamara L Lotan.

The MiT/TFE family gene fusion proteins, such as SFPQ-TFE3 , drive both epithelial (eg, translocation renal cell carcinoma, tRCC) and mesenchymal (eg, perivascular epithelioid cell tumor, PEComa) neoplasms with aggressive behavior. However, no prior mouse models for SFPQ-TFE3 -related tumors exist and the mechanisms of lineage plasticity induced by this fusion remain unclear. Here, we demonstrate that constitutive murine renal expression of human SFPQ-TFE3 using Ksp Cadherin-Cre as a driver disrupts kidney development leading to early neonatal renal failure and death. In contrast, post-natal induction of SFPQ-TFE3 in renal tubular epithelial cells using Pax8 ERT-Cre induces infiltrative epithelioid tumors, which morphologically and transcriptionally resemble human PEComas. As seen in MiT/TFE fusion-driven human tumors, SFPQ-TFE3 expression is accompanied by the strong induction of mTORC1 signaling, which is partially amino acid-sensitive and dependent on increased SFPQ-TFE3 -mediated RRAGC/D transcription. Remarkably, SFPQ-TFE3 expression is sufficient to induce lineage plasticity in renal tubular epithelial cells, with rapid down-regulation of the critical PAX2/PAX8 nephric lineage factors and tubular epithelial markers, and concomitant up-regulation of PEComa differentiation markers in transgenic mice, human cell line models and human tRCC. Pharmacologic or genetic inhibition of mTOR signaling downregulates expression of the SFPQ-TFE3 fusion protein and rescues nephric lineage marker expression and transcriptional activity in vitro. These data provide evidence of a potential epithelial cell-of-origin for TFE3 -driven PEComas and highlight a reciprocal role for SFPQ-TFE3 and mTOR in driving lineage plasticity in the kidney, expanding our understanding of the pathogenesis of MiT/TFE-driven tumors.

DOI: https://doi.org/10.1101/2024.11.21.624702

Front Biosci (Landmark Ed). 2024 Nov 20. 29(11): 393

Dual Role of Lysosome in Cancer Development and Progression.

Xiao-Qiong Chen, Quan Yang, Wei-Min Chen, Zi-Wei Chen, Guang-Hui Guo, Xuan Zhang, Xiao-Ming Sun, Tao Shen, Fu-Hui Xiao, Yun-Feng Li.

Lysosomes are essential intracellular catabolic organelles that contain digestive enzymes involved in the degradation and recycle of damaged proteins, organelles, etc. Thus, they play an important role in various biological processes, including autophagy regulation, ion homeostasis, cell death, cell senescence. A myriad of studies has shown that the dysfunction of lysosome is implicated in human aging and various age-related diseases, including cancer. However, what is noteworthy is that the modulation of lysosome-based signaling and degradation has both the cancer-suppressive and cancer-promotive functions in diverse cancers depending on stage, biology, or tumor microenvironment. This dual role limits their application as targets in cancer therapy. In this review, we provide an overview of lysosome and autophagy-lysosomal pathway and outline their critical roles in many cellular processes, including cell death. We highlight the different functions of autophagy-lysosomal pathway in cancer development and progression, underscoring its potential as a target for effective cancer therapies.

Keywords: autophagy; cancer; cell death; cell senescence; lysosome

DOI: https://doi.org/10.31083/j.fbl2911393

Oncol Rev. 2024 ;18 1434981

Construction methods and latest applications of kidney cancer organoids.

Zhiqiang Li, Yanqiu You, Bingzheng Feng, Jibing Chen, Hongjun Gao, Fujun Li.

Renal cell carcinoma (RCC) is one of the deadliest malignant tumors. Despite significant advances in RCC treatment over the past decade, complete remission is rarely achieved. Consequently, there is an urgent need to explore and develop new therapies to improve the survival rates and quality of life for patients. In recent years, the development of tumor organoid technology has attracted widespread attention as it can more accurately simulate the spatial structure and physiological characteristics of tumors within the human body. In this review, we summarize the main methods currently used to construct kidney cancer organoids, as well as their various biological and clinical applications. Furthermore, combining organoids with other technologies, such as co-culture techniques and microfluidic technologies, can further develop organoids and address their limitations, creating more practical models. This approach summarizes the interactions between different tissues or organs during tumor progression. Finally, we also provide an outlook on the construction and application of kidney cancer organoids. These rapidly evolving kidney cancer organoids may soon become a focal point in the development of in vitro clinical models and therapeutic research for kidney cancer.

Keywords: co-culture; drug screening; microfluidic device; organoid; personalized treatment; renal cell carcinoma; tumor microenvironment

DOI: https://doi.org/10.3389/or.2024.1434981