Signal peptide peptidase and SPP-like proteases - Possible therapeutic targets?

Mentrup, Torben; Loock, Ann-Christine; Fluhrer, Regina; Schröder, Bernd

doi:10.1016/j.bbamcr.2017.06.007

Cited by 25 publications

(30 citation statements)

References 162 publications

(330 reference statements)

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“…Similar to our results, an extensive study of the human proteome identified SPPL2c only in testis [38]. Based on the published phenotypes of SPPL2a/b-and SPPL3-deficient mice, these proteases play a significant role in the immune system [7]. In this regard, the newly described role of SPPL2c extends the in vivo relevance of SPP/SPPL to the reproductive system.…”

Section: Discussionsupporting

confidence: 88%

“…The inhibitory profile of SPPL2c indicates two remarkable differences with regard to other SPP/SPPL proteases. In the performed RAMP4-2 cleavage assay, SPPL2c was not inhibited by the active site inhibitor (Z-LL) 2 -ketone, which acts on all SPP/SPPL proteases with the exception of SPPL3 [4,7,25,28]. In contrast, the c-secretase inhibitor DAPT partially blocked cleavage by SPPL2c.…”

Section: Discussionmentioning

confidence: 92%

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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: 88%

Section: Discussionmentioning

confidence: 92%

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

et al. 2019

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“…Signal peptide peptidases (SPPs) and the related signal peptide peptidase‐like (SPPL) proteases are a family of GxGD‐type intramembrane aspartyl proteases that were identified in search of homologs to presenilin, the catalytically active subunit of gamma secretase. These polytopic membrane proteins are known to cleave Type II (N in ) and Type IV tail‐anchored proteins.…”

Section: Distinct Intramembrane Proteases Are Located In the Er (Spp mentioning

confidence: 99%

Regulating the regulator: intramembrane proteolysis of vesicular trafficking proteins and the SERCA regulator phospholamban

Young

Lemieux

2019

EMBO Reports

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Intramembrane proteases reside within the subcellular compartments of cells to carry out a multiplicity of functions. One such family is the signal peptide peptidase (SPP) and signal peptide peptidase‐like (SPPL) family. The SPP/SPPL family comprises several homologs of aspartyl‐intramembrane proteases, and recent studies demonstrate distinct compartmentalization for each and a largely unknown cadre of substrates. Due to their hydrophobic nature, identification of substrates for intramembrane proteases can be an arduous task. In this issue of EMBO Reports, two studies identify physiological substrates of SPPL2c (1, 2). SPPL2c targets a variety of SNARE proteins, thereby playing a significant role in vesicular transport from the ER and in turn influencing the composition of the Golgi. Furthermore, trafficking defects observed in SPPL2c lacking cells lead to morphological changes in the spermatid cells of the testes, the only known site of protein expression. In these cells, phospholamban, a single‐pass transmembrane regulator of the Ca2+ transporter SERCA, was also identified as an SPPL2c substrate that impacts Ca2+ storage. This may explain the SPPL2c effect on germ cell development.

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“…As recently reviewed [13], SPP plays a role in different viral infections by being involved in the processing and thereby maturation of different viral proteins. By this means, the SPP activity of the host cell is a critical factor for viral replication.…”

Section: Viral Infectionsmentioning

confidence: 99%

“…This process significantly profited from existing compounds initially generated for inhibition of the related γ-secretase for treatment of Alzheimer's disease and leukaemia [113]. While some of these inhibitors appear to selectively target γ-secretase and spare the SPP/SPPL family, others like L-685,458 and LY-411575 also inhibit processing of SPP/SPPL substrates even though with different efficiency for individual proteases [13,114,115]. In this context, it was an interesting observation that SPPL2c activity is targeted by DAPT [18], a well-established γ-secretase inhibitor (GSI) that spares all other SPP/SPPL proteases [13] strongly arguing for major differences between SPPL2c and the other family members.…”

Section: Recent Advances In Spp/sppl Inhibitor Developmentmentioning

confidence: 99%

Physiological functions of SPP/SPPL intramembrane proteases

Mentrup

Cabrera-Cabrera

Fluhrer

et al. 2020

Cell. Mol. Life Sci.

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Intramembrane proteolysis describes the cleavage of substrate proteins within their hydrophobic transmembrane segments. Several families of intramembrane proteases have been identified including the aspartyl proteases Signal peptide peptidase (SPP) and its homologues, the SPP-like (SPPL) proteases SPPL2a, SPPL2b, SPPL2c and SPPL3. As presenilin homologues, they employ a similar catalytic mechanism as the well-studied γ-secretase. However, SPP/SPPL proteases cleave transmembrane proteins with a type II topology. The characterisation of SPP/SPPL-deficient mouse models has highlighted a still growing spectrum of biological functions and also promoted the substrate discovery of these proteases. In this review, we will summarise the current hypotheses how phenotypes of these mouse models are linked to the molecular function of the enzymes. At the cellular level, SPP/SPPL-mediated cleavage events rather provide specific regulatory switches than unspecific bulk proteolysis. By this means, a plethora of different cell biological pathways is influenced including signal transduction, membrane trafficking and protein glycosylation.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Signal peptide peptidase and SPP-like proteases - Possible therapeutic targets?

Cited by 25 publications

References 162 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

Regulating the regulator: intramembrane proteolysis of vesicular trafficking proteins and the SERCA regulator phospholamban

Physiological functions of SPP/SPPL intramembrane proteases

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