Zinc-Dependent Lysosomal Enlargement in TRPML1-Deficient Cells Involves MTF-1 Transcription Factor and ZnT4 (Slc30a4) Transporter

Zn is critical for a multitude of cellular processes, including gene expression, secretion and enzymatic activities. Cellular Zn is controlled by Zn-chelating proteins and by Zn transporters. The recent identification of Zn permeability of the lysosomal ion channel TRPML1, and the evidence of abnormal Zn levels in cells deficient in TRPML1, suggested a role for TRPML1 in Zn transport. Here we provide new evidence for such a role and identify additional cellular components responsible for it. In agreement with the previously published data, an acute siRNA-driven TRPML1 knockdown (KD) leads to the buildup of large cytoplasmic vesicles positive for Lysotracker and Zn staining, when cells are exposed to high concentrations of Zn. We now show that lysosomal enlargement and Zn buildup in TRPML1-KD cells exposed to Zn are ameliorated by KD of the Zn-sensitive transcription factor MTF-1 or Zn transporter ZnT4. TRPML1 KD is associated with a buildup of cytoplasmic Zn and with enhanced transcriptional response of mRNA for metallothionein 2a (MT2a). TRPML1 KD did not suppress lysosomal secretion, but it did delay Zn leak from the lysosomes into the cytoplasm. These data underscore a role for TRPML1 in Zn metabolism. Furthermore, they suggest that TRPML1 works in concert with ZnT4 to regulate Zn translocation between the cytoplasm and lysosomes.
Source: BJ Cell - Category: Biochemistry Authors: Tags: BJ Cell Source Type: research