Disrupted in renal carcinoma 2 (DIRC2), a novel transporter of the lysosomal membrane, is proteolytically processed by cathepsin L.

DIRC2 (Disrupted in renal carcinoma 2) has been initially identified as a breakpoint-spanning gene in a chromosomal translocation putatively associated with the development of renal cancer. The DIRC2 protein belongs to the MFS (major facilitator superfamily) and has been previously detected by organellar proteomics as a tentative constituent of lysosomal membranes. In the present study, lysosomal residence of overexpressed as well as endogenous DIRC2 was shown by several approaches.

The proteome of lysosomes.

Lysosomes are organelles of eukaryotic cells that are critically involved in the degradation of macromolecules mainly delivered by endocytosis and autophagocytosis. Degradation is achieved by more than 60 hydrolases sequestered by a single phospholipid bilayer. The lysosomal membrane facilitates interaction and fusion with other compartments and harbours transport proteins catalysing the export of catabolites, thereby allowing their recycling.

Molecular characterisation of 'transmembrane protein 192' (TMEM192), a novel protein of the lysosomal membrane.

Transmembrane protein 192 (TMEM192) has been previously identified in proteomic analyses of lysosomal membranes. TMEM192 does not exhibit any significant homology to known protein families and possesses four potential transmembrane segments. To approach the molecular role of TMEM192, a detailed biochemical characterisation of this protein was performed.

Integral and associated lysosomal membrane proteins.

We searched for novel proteins in lysosomal membranes, tentatively participating in molecular transport across the membrane and/or in interactions with other compartments. In membranes purified from placental lysosomes, we identified 58 proteins, known to reside at least partially in the lysosomal membrane. These included 17 polypeptides comprising or associated with the vacuolar adenosine triphosphatase.

Neutrophil elastase is associated with serglycin on its way to lysosomes in U937 cells.

Mutations in the neutrophil elastase (NE) gene have been postulated to interfere with normal intracellular trafficking of NE as an AP3-interacting membrane integrated protein and to cause severe congenital or cyclic neutropenia in humans. Here, we show that in U937 promonocytes NE is synthesized as a predominantly soluble proenzyme and is completely secreted in the presence of phorbol esters similarly to serglycin. Using chemical cross-linking NE is shown to be associated with serglycin as 34 kDa proenzyme in the trans-Golgi region of these cells indicating that it is delivered to lysosomes associated with serglycin.

Increased menin expression in sporadic pituitary adenomas.

Background: Germline mutations of the multiple endocrine neoplasia type 1 (MEN1) tumour-suppressor gene are responsible for multiple endocrine neoplasia type 1, and menin, the MEN1 gene product, is usually downregulated or truncated in MEN1-associated adenomas. In contrast, exonic MEN1 mutations seem to be very rare in sporadic (MEN1-unrelated) pituitary adenomas, and it has been suggested that menin does not play a major role in these tumours. However, menin might be involved in sporadic adenoma tumorigenesis by downregulation through intronic mutations, epigenetic, posttranscriptional or posttranslational mechanisms.