TTYH3 regulates lysosomal chloride currents, cellular clearance, and markers of cellular senescence
TTYH3 regulates lysosomal chloride currents, cellular clearance, and markers of cellular senescence
On July 17, Cell Reports published a study of TTYH3, a protein found in the membrane of lysosomes, the intracellular vesicles that break down and recycle molecules. In cell experiments, TTYH3 was linked to chloride transport, autophagy, which is the cell's internal clearance system, and markers of cellular senescence.
In the new study, Chunlei Cang's group investigated a specific question: which protein, besides the known CLN7 channel, supports chloride currents across the lysosomal membrane? This current persisted in some lysosomes from cells lacking CLN7. The authors attributed the remaining current to TTYH3, a lysosomal membrane protein.
The authors measured the chloride current, but have not yet established whether TTYH3 forms the channel pore itself or regulates another protein.
Lysosomes contain a high concentration of chloride. When TTYH3 was overexpressed, lysosomal calcium levels decreased. Blocking TRPML1, the channel through which calcium leaves the lysosome, reduced the lysosomal fusion induced by TTYH3. The authors interpret these results as evidence that the effect involves calcium release through TRPML1.
TTYH3 also reduced the phosphorylation of proteins in the AKT/mTOR signaling pathway, which suppresses autophagy. TFEB, a regulatory protein that controls the cellular clearance program, was found more often in the nucleus, and other measurements indicated increased autophagic flux.
In a 2021 study, the same line of research showed that CLN7 functions as a lysosomal chloride channel. In cells, TTYH3 overexpression partially corrected the effects of CLN7 deficiency: it restored chloride currents, normalized lysosomal pH, and reduced oxidative lipid damage and cellular autofluorescence.
The authors examined the link to aging in human SH-SY5Y neuroblastoma cells. TTYH3 knockdown increased the levels of p53 and p21, proteins that stop cell division, and increased the proportion of cells expressing a marker of cellular senescence. The active form of the signaling protein ERK partially reversed the effects of TTYH3 knockdown. TTYH3 abundance declined with age in the mouse brain, but the researchers measured only protein levels in this experiment.
In living organisms, TTYH3 has so far been studied only by measuring its abundance in the mouse brain. The authors propose tissue-specific knockout of the TTYH3 gene in mice to test its role in neurodegeneration and lifespan regulation. In a study of ASAP3, knockout of another autophagy regulator in mice was associated with fewer markers of liver aging and a longer lifespan.