In Aging Cell, researchers have explained how transcription factor EB (TFEB) is related to cellular senescence and keeps stressed cells alive.
Inactivated by mTOR
Yesterday, we reported on TFEB’s effects on proteostasis and how it has downstream functions on protein chaperones. This research, however, focuses on an somewhat different aspect of this transcription factor: its effects on the lysosomes that digest unwanted proteins and its role in autophagy, the process by which cells consume their own organelles as a maintenance process [1].
Previous work has found that mTOR has effects on TFEB, phosphorlyating it and rendering it inactive within the cytosol of the cells. Reversing this process leads to the activation of a gene network that alters lysosomal function. When nutrients are abundant, mTOR kicks in; when there are fewer nutrients or when the lysosome is stressed, TFEB becomes active [1].
The researchers note a documented oddity in mTOR’s function and reactions. During senescence, it activates components of the SASP [2]. However, the stresses associated with senescence also render mTOR inactive, thus activating TFEB; this has been suggested to be a reason why senescent cells stay alive [3]. This work, therefore, was done to codify the relationship between mTOR, TFEB, cellular senescence, and oxidative stress sensors.
Surviving the storm
For their first experiment, the researchers chemically induced senescence in a population of human dermal fibroblasts, which are commonly used in senescence studies. Four days of twice-daily administration of this toxin put the cells under significant stress (the “stress phase”), driving them senescent five days after that.
The researchers found that the lysosomes were highly activated during the stress phase, but by the time the cells became fully senescent, this overactivation had ceased. Similar results were found when ultraviolet radiation was used to drive cells senescent instead of a chemical.
The stressed cells were clearly having problems performing autophagy. The researchers found that autophagic flux, a measurement of this maintenance process, decreases when the lysosomes are stressed. Removing the stressors allows the return of proper autophagy, even when the cells have been driven to senescence.
During the stress phase, TFEB was found to be in the nucleus, becoming activated while mTOR was found to be deactivated. However, during senescence, TFEB was found to reside inactivated in the cytosol, presumably due to the effects of mTOR. The transcription factor that had allowed these cells to survive to senescence had no need to be active when they were actually senescent.
Both of the oxidative stress indicators AMPK and Akt affect mTOR. Just like TFEB, AMPK activation was increased during the stress phase but dwindled during senescence. Akt, on the other hand, decreased during stress and increased during senescence instead. These findings dovetail with previous work showing a signaling relationship between AMPK and Akt [4].
More TFEB means more survival and more senescence
The researchers created cells that overexpress TFEB. Compared to a control group, more of these cells survived the chemical that drove them senescent, preventing far more deaths by apoptosis. However, despite their increased survival rate, these cells progressed into senescence. As expected, depleting TFEB decreased the cells’ ability to survive.
Crucially, there appears to be no truly direct link between TFEB and senescence, as senescence-related pathways were unaffected by its depletion. TFEB is a cellular survival mechanism; the fact that the cells survive to become senescent is not within its biochemical purview.
The researchers float the idea that TFEB inhibitors could be used as a pre-senolytic, causing stressed cells to die rather than linger around excreting the inflammatory SASP. However, given TFEB’s effects on other cells, such an inhibitor would need to be precisely targeted.
Literature
[1] Napolitano, G., & Ballabio, A. (2016). TFEB at a glance. Journal of cell science, 129(13), 2475-2481.
[2] Carroll, B., Nelson, G., Rabanal-Ruiz, Y., Kucheryavenko, O., Dunhill-Turner, N. A., Chesterman, C. C., … & Korolchuk, V. I. (2017). Persistent mTORC1 signaling in cell senescence results from defects in amino acid and growth factor sensing. Journal of Cell Biology, 216(7), 1949-1957.
[3] Curnock, R., Yalci, K., Palmfeldt, J., Jäättelä, M., Liu, B., & Carroll, B. (2023). TFEB‐dependent lysosome biogenesis is required for senescence. The EMBO journal, 42(9), e111241.
[4] Zhao, Y., Hu, X., Liu, Y., Dong, S., Wen, Z., He, W., … & Shi, M. (2017). ROS signaling under metabolic stress: cross-talk between AMPK and AKT pathway. Molecular cancer, 16, 1-12.
