Signal peptide peptidase‐like 2c impairs vesicular transport and cleaves SNARE proteins

Papadopoulou, Alkmini A; Müller, Stephan; Mentrup, Torben; Shmueli, Merav D.; Niemeyer, Johannes; Haug-Kröper, Martina; Blume, Julia von; Mayerhofer, Artur; Feederle, Regina; Schröder, Bernd; Lichtenthaler, Stefan F.; Fluhrer, Regina

doi:10.15252/embr.201846451

Cited by 28 publications

(69 citation statements)

References 52 publications

(107 reference statements)

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“…As identified in a cell‐based substrate screen utilising SPPL2c overexpression, SPPL2c is capable of processing selected SNARE proteins of the early secretory pathway. Overlapping with the substrates revealed by Papadopoulou et al , we observed an accumulation of STX8 in SPPL2c‐deficient testis in our proteomic analysis. It seems likely that other relevant substrates have escaped our proteomic screening since the effect of SPPL2c deficiency in the analysis of total testis membrane preparations has been diluted by non‐ or low‐SPPL2c‐expressing cells.…”

Section: Discussionsupporting

confidence: 79%

“…Like SPP, SPPL2c co‐expression efficiently reduced overall levels of murine HO‐1 (Fig A). In support, HO‐1 was also identified in a proteomic substrate screen in SPPL2c‐overexpressing HEK cells (accompanying manuscript by Papadopoulou et al ). Upon co‐expression of human HO‐1 with the murine proteases, even a potential cleavage product with a slightly lower molecular weight was detected (Fig EV3A).…”

Section: Resultsmentioning

confidence: 76%

“…Finally, we investigated whether our findings describing a novel role of SPPL2c in male germ cell development in mice may also have implications in humans. Using the antiserum against murine SPPL2c, which cross‐reacts with the human protein, and a novel human‐specific SPPL2c monoclonal antibody , we demonstrate endogenous expression of SPPL2c in human testis lysates (Fig H). Furthermore, also human SPPL2c was detected in elongated spermatids (Fig I).…”

Section: Resultsmentioning

confidence: 93%

“…In contrast, STX8 and PLN are TA proteins and thus fulfil the basic requirements of representing candidate substrates. STX8 was also identified in an overexpression‐based SPPL2c substrate screen and could be further validated as SPPL2c substrate .…”

Section: Resultsmentioning

confidence: 99%

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The intramembrane protease SPPL 2c promotes male germ cell development by cleaving phospholamban

et al. 2019

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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 Ca2+‐ATPase (SERCA2)‐regulating protein phospholamban (PLN) as a physiological SPPL2c substrate. Accumulation of PLN correlates with a decrease in intracellular Ca2+ levels in elongated spermatids that likely contribute to the compromised male germ cell differentiation and function of SPPL2c−/− mice.

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Section: Discussionsupporting

confidence: 79%

Section: Resultsmentioning

confidence: 76%

Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

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The intramembrane protease SPPL 2c promotes male germ cell development by cleaving phospholamban

et al. 2019

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“…Peptide analysis of the secreted enzymes revealed that the cleavage site was within the TMD towards the lumenal face with a preference for M or Y residues at position one . While it appears that SPPL3 is the primary protease responsible for the cleavage of Golgi enzymes, similar analyses of the secretome of BACE1‐inhibited and SPPL2C‐overexpressing cells revealed a handful of Golgi enzyme substrates for these proteases, some of which were shared with SPPL3 . This suggests that some enzymes are subject to cleavage by multiple different proteases.…”

Section: Secretion Of Golgi Enzymesmentioning

confidence: 99%

A tale of short tails, through thick and thin: investigating the sorting mechanisms of Golgi enzymes

Welch

Munro

2019

FEBS Letters

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The Golgi apparatus is an important site for the modification of most secreted and membrane proteins. Glycan processing is the major class of modification and is mediated by a large number of Golgi‐resident glycosyltransferases and glycosidases. These Golgi enzymes are largely type II transmembrane domain (TMD) proteins consisting of a short N‐terminal cytosolic tail, a relatively short TMD and a lumenal ‘stem/stalk’ region which acts as a spacer between the catalytic domain and the lipid bilayer. The cytosolic tail, TMD, and stem together make what is termed the CTS domain which is responsible for the specific localisation of these enzymes within sub‐Golgi compartments via multiple mechanisms. In addition, the catalytic domains of some Golgi enzymes are secreted as a consequence of proteolytic cleavage within their TMDs or stem regions. Finally, there is evidence to suggest that when the retention of Golgi enzymes is perturbed they are targeted for lysosomal degradation.

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Genetic Regulation of Immunoglobulin G Glycosylation

Frkatović

Zaytseva

Klarić

2021

Experientia Supplementum

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Signal peptide peptidase‐like 2c impairs vesicular transport and cleaves SNARE proteins

Cited by 28 publications

References 52 publications

The intramembrane protease SPPL 2c promotes male germ cell development by cleaving phospholamban

The intramembrane protease SPPL 2c promotes male germ cell development by cleaving phospholamban

A tale of short tails, through thick and thin: investigating the sorting mechanisms of Golgi enzymes

Genetic Regulation of Immunoglobulin G Glycosylation

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