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74 Publications visible to you, out of a total of 74
Signal peptide peptidase-like 2c impairs vesicular transport and cleaves SNARE proteins.

Abstract (Expand)

Members of the GxGD-type intramembrane aspartyl proteases have emerged as key players not only in fundamental cellular processes such as B-cell development or protein glycosylation, but also in development … of pathologies, such as Alzheimer's disease or hepatitis virus infections. However, one member of this protease family, signal peptide peptidase-like 2c (SPPL2c), remains orphan and its capability of proteolysis as well as its physiological function is still enigmatic. Here, we demonstrate that SPPL2c is catalytically active and identify a variety of SPPL2c candidate substrates using proteomics. The majority of the SPPL2c candidate substrates cluster to the biological process of vesicular trafficking. Analysis of selected SNARE proteins reveals proteolytic processing by SPPL2c that impairs vesicular transport and causes retention of cargo proteins in the endoplasmic reticulum. As a consequence, the integrity of subcellular compartments, in particular the Golgi, is disturbed. Together with a strikingly high physiological SPPL2c expression in testis, our data suggest involvement of SPPL2c in acrosome formation during spermatogenesis.

Authors: A. A. Papadopoulou, S. A. Muller, T. Mentrup, M. D. Shmueli, J. Niemeyer, M. Haug-Kroper, J. von Blume, A. Mayerhofer, R. Feederle, B. Schroder, S. F. Lichtenthaler, R. Fluhrer

Date Published: 9th Feb 2019

Publication Type: Journal

The intramembrane protease SPPL2c promotes male germ cell development by cleaving phospholamban.

Abstract (Expand)

Signal peptide peptidase (SPP) and the four homologous SPP-like (SPPL) proteases constitute a family of intramembrane aspartyl proteases with selectivity for type II-oriented transmembrane segments. … Here, we analyse the physiological function of the orphan protease SPPL2c, previously considered to represent a non-expressed pseudogene. We demonstrate proteolytic activity of SPPL2c towards selected tail-anchored proteins. Despite shared ER localisation, SPPL2c and SPP exhibit distinct, though partially overlapping substrate spectra and inhibitory profiles, and are organised in different high molecular weight complexes. Interestingly, SPPL2c is specifically expressed in murine and human testis where it is primarily localised in spermatids. In mice, SPPL2c deficiency leads to a partial loss of elongated spermatids and reduced motility of mature spermatozoa, but preserved fertility. However, matings of male and female SPPL2c(-/-) mice exhibit reduced litter sizes. Using proteomics we identify the sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA2)-regulating protein phospholamban (PLN) as a physiological SPPL2c substrate. Accumulation of PLN correlates with a decrease in intracellular Ca(2+) levels in elongated spermatids that likely contribute to the compromised male germ cell differentiation and function of SPPL2c(-/-) mice.

Authors: J. Niemeyer, T. Mentrup, R. Heidasch, S. A. Muller, U. Biswas, R. Meyer, A. A. Papadopoulou, V. Dederer, M. Haug-Kroper, V. Adamski, R. Lullmann-Rauch, M. Bergmann, A. Mayerhofer, P. Saftig, G. Wennemuth, R. Jessberger, R. Fluhrer, S. F. Lichtenthaler, M. K. Lemberg, B. Schroder

Date Published: 9th Feb 2019

Publication Type: Journal

Autophagy acts through TRAF3 and RELB to regulate gene expression via antagonism of SMAD proteins.

Abstract (Expand)

Macroautophagy can regulate cell signalling and tumorigenesis via elusive molecular mechanisms. We establish a RAS mutant cancer cell model where the autophagy gene ATG5 is dispensable in A549 cells … in vitro, yet promotes tumorigenesis in mice. ATG5 represses transcriptional activation by the TGFbeta-SMAD gene regulatory pathway. However, autophagy does not terminate cytosolic signal transduction by TGFbeta. Instead, we use proteomics to identify selective degradation of the signalling scaffold TRAF3. TRAF3 autophagy is driven by RAS and results in activation of the NF-kappaB family member RELB. We show that RELB represses TGFbeta target promoters independently of DNA binding at NF-kappaB recognition sequences, instead binding with SMAD family member(s) at SMAD-response elements. Thus, autophagy antagonises TGFbeta gene expression. Finally, autophagy-deficient A549 cells regain tumorigenicity upon SMAD4 knockdown. Thus, at least in this setting, a physiologic function for autophagic regulation of gene expression is tumour growth.

Authors: A. C. Newman, A. J. Kemp, Y. Drabsch, C. Behrends, S. Wilkinson

Date Published: 16th Nov 2017

Publication Type: Journal

Autophagosomal Content Profiling Reveals an LC3C-Dependent Piecemeal Mitophagy Pathway.

Abstract (Expand)

Autophagy allows the degradation of cytosolic endogenous and exogenous material in the lysosome. Substrates are engulfed by double-membrane vesicles, coined autophagosomes, which subsequently fuse with … lysosomes. Depending on the involvement of specific receptor proteins, autophagy occurs in a selective or nonselective manner. While this process is well understood at the level of bulky cargo such as mitochondria and bacteria, we know very little about individual proteins and protein complexes that are engulfed and degraded by autophagy. In contrast to the critical role of autophagy in balancing proteostasis, our current knowledge of the autophagic degradome is very limited. Here, we combined proximity labeling with quantitative proteomics to systematically map the protein inventory of autophagosomes. Using this strategy, we uncovered a basal, housekeeping mitophagy pathway that involves piecemeal degradation of mitochondrial proteins in a LC3C- and p62-dependent manner and contributes to mitochondrial homeostasis maintenance when cells rely on oxidative phosphorylation.

Authors: F. Le Guerroue, F. Eck, J. Jung, T. Starzetz, M. Mittelbronn, M. Kaulich, C. Behrends

Date Published: 16th Nov 2017

Publication Type: Journal

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