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

Savalas, Lalu Rudyat Telly; Gasnier, Bruno; Damme, Markus; Lübke, Torben; Wrocklage, Christian; Debacker, Cécile; Jézégou, Adrien; Reinheckel, Thomas; Hasilík, Andrej; Säftig, Paul; Schröder, Bernd

doi:10.1042/bj20110166

Cited by 31 publications

(35 citation statements)

References 49 publications

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“…Fixation with 4% (w/v) paraformaldehyde in PBS and immunocytochemical staining was performed as described [18]. CD74 was visualised using the monoclonal antibody PIN1 detecting the full-length protein and the CD74 NTF.…”

Section: Methodsmentioning

confidence: 99%

Signal-peptide-peptidase-like 2a is required for CD74 intramembrane proteolysis in human B cells

Schneppenheim

Hüttl

Kruchen

et al. 2014

Biochemical and Biophysical Research Communications

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The invariant chain (CD74) mediates targeting of the MHCII complex to endosomal compartments, where CD74 undergoes degradation allowing MHCII to acquire peptides. We demonstrated recently that intramembrane proteolysis of the final membrane-bound N-terminal fragment (NTF) of CD74 is catalysed by Signal-peptide-peptidase-like 2a (SPPL2a) and that this process is indispensable for development and function of B lymphocytes in mice. In SPPL2a−/− mice, homeostasis of these cells is disturbed by the accumulation of the unprocessed CD74 NTF. So far, evidence for this essential role of SPPL2a is restricted to mice. Nevertheless, inhibition of SPPL2a has been suggested as novel approach to target B cells for treating autoimmunity. Here, we characterize human B cell lines with a homozygous microdeletion on chromosome 15. We demonstrate that this deletion disrupts the SPPL2a genomic locus and leads to loss of SPPL2a transcript. Lymphoblastoid cell lines from patients with this deletion exhibit absence of SPPL2a at the protein level and show an accumulation of the CD74 NTF comparable to B cells from SPPL2a−/− mice. By this means, we present evidence that the role of SPPL2a in CD74 proteolysis is conserved in human B cells and provide support for modulation of SPPL2a activity as a therapeutic concept.

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Section: Methodsmentioning

confidence: 99%

Signal-peptide-peptidase-like 2a is required for CD74 intramembrane proteolysis in human B cells

Schneppenheim

Hüttl

Kruchen

et al. 2014

Biochemical and Biophysical Research Communications

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“…Tritosome preparation was performed as described previously [11,22]. Livers were prepared according to european guidelines for the care and use of experimental animals.…”

Section: Tritosome Preparationmentioning

confidence: 99%

Lysosomal integral membrane protein type-2 (LIMP-2/SCARB2) is a substrate of cathepsin-F, a cysteine protease mutated in type-B-Kufs-disease

Peters

Rittger

Knabbe

et al. 2015

Biochemical and Biophysical Research Communications

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“…This protein set contains numerous subunits of ATPases (v-ATPase (n ϭ 6); P-ATPases (n ϭ 5)), ATP-binding cassette (ABC) transporters (n ϭ 9), channels (n ϭ 10), and secondary active transporters (n ϭ 42). The latter include the recently discovered potential or effective lysosomal transporters C2ORF18 (21, 51), DIRC2 (27), LMBD1 (52), and MFSD8 (53) (Fig. 6).…”

Section: Fig 1 Workflow Of the Sample Preparation For Ms Analysismentioning

confidence: 99%

An Extended Proteome Map of the Lysosomal Membrane Reveals Novel Potential Transporters

Chapel¹,

Kieffer‐Jaquinod²,

Sagné³

et al. 2013

Molecular & Cellular Proteomics

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160

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Lysosomes are membrane-bound endocytic organelles that play a major role in degrading cell macromolecules and recycling their building blocks. A comprehensive knowledge of the lysosome function requires an extensive description of its content, an issue partially addressed by previous proteomic analyses. However, the proteins underlying many lysosomal membrane functions, including numerous membrane transporters, remain unidentified. We performed a comparative, semi-quantitative proteomic analysis of rat liver lysosome-enriched and lysosome-nonenriched membranes and used spectral counts to evaluate the relative abundance of proteins. Among a total of 2,385 identified proteins, 734 proteins were significantly enriched in the lysosomal fraction, including 207 proteins already known or predicted as endo-lysosomal and 94 proteins without any known or predicted subcellular localization. The remaining 433 proteins had been previously assigned to other subcellular compartments but may in fact reside on lysosomes either predominantly or as a secondary location. Many membrane-associated complexes implicated in diverse processes such as degradation, membrane trafficking, lysosome biogenesis, lysosome acidification, signaling, and nutrient sensing were enriched in the lysosomal fraction. They were identified to an unprecedented extent as most, if not all, of their subunits were found and retained by our screen. Numerous transporters were also identified, including 46 novel potentially lysosomal proteins. We expressed 12 candidates in HeLa cells and observed that most of them colocalized with the lysosomal marker LAMP1, thus confirming their lysosomal residency. This list of candidate lysosomal proteins substantially increases our knowledge of the lysosomal membrane and provides a basis for further characterization of lysosomal functions. Molecular & Cellular

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

Cited by 31 publications

References 49 publications

Signal-peptide-peptidase-like 2a is required for CD74 intramembrane proteolysis in human B cells

Signal-peptide-peptidase-like 2a is required for CD74 intramembrane proteolysis in human B cells

Lysosomal integral membrane protein type-2 (LIMP-2/SCARB2) is a substrate of cathepsin-F, a cysteine protease mutated in type-B-Kufs-disease

An Extended Proteome Map of the Lysosomal Membrane Reveals Novel Potential Transporters

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