Specialized Protein TFEB May be Key to Understanding LAM

Tuberous Sclerosis Complex (TSC) is a genetic disorder caused by mutations in the TSC1 or TSC2 gene, leading to the hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1). This hyperactivation results in disease in multiple organs, including the lungs (lymphangioleiomyomatosis, or LAM) and kidneys (angiomyolipomas).

Our study found that Transcription Factor EB (TFEB) is a critical factor driving kidney disease in a mouse model TSC. TFEB is a specialized protein called a transcription factor. Transcription factors bind to DNA and regulate many (often hundreds) of genes. TFEB increases the production of lysosomes and lysosomal enzymes. Lysosomes, sometimes referred to as cellular garbage disposals, degrade and recycle unneeded cellular material and proteins. Lysosomes contain powerful enzymes such as Cathepsin K to break down proteins.

In a new mouse model of TSC, we found severe kidney lesions, with many lysosomes. When TFEB was genetically removed, or “knocked out,” the kidneys became almost normal. This indicates that excess TFEB activity causes kidney disease in these mice.

As expected,  mTORC1 activity in the TSC2-deficient kidneys was elevated. Unexpectedly, the mTORC1 activity was restored to normal levels by the knockout of TFEB. Previously, TFEB was not known to control mTORC1 activity in TSC. These findings challenge our understanding of why mTORC1 is active in LAM and TSC.

Excess nuclear TFEB and lysosomal activity may also be important in LAM. The lysosomal enzyme Cathepsin K is a hallmark of LAM cells.  A buildup of lysosomes, due to TFEB activity, could contribute to lung cysts in LAM.  Further research is needed to test this.

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