Signal peptide peptidase-like 2 proteases: Regulatory switches or proteasome of the membrane?

Mentrup, Torben; Schröder, Bernd

doi:10.1016/j.bbamcr.2021.119163

Cited by 7 publications

(24 citation statements)

References 111 publications

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“…HA-tagged expression constructs. Cleavage of TA proteins by SPPL2a/b seems to be highly selective, which is in line with previous findings for SPP and SPPL2c [1]. Apparently, TA topology and co-localisation with the protease within the same subcellular compartment are required but not sufficient preconditions for cleavage.…”

Section: Discussionsupporting

confidence: 90%

“…Despite its localisation in late endosomes and lysosomes [21], VAMP7 is missing in this analysis as we failed to achieve sufficient expression levels using HA‐tagged expression constructs. Cleavage of TA proteins by SPPL2a/b seems to be highly selective, which is in line with previous findings for SPP and SPPL2c [1]. Apparently, TA topology and co‐localisation with the protease within the same subcellular compartment are required but not sufficient preconditions for cleavage.…”

Section: Discussionsupporting

confidence: 90%

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The intramembrane proteases SPPL2a and SPPL2b regulate the homeostasis of selected SNARE proteins

et al. 2022

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Signal peptide peptidase (SPP) and SPP‐like (SPPL) aspartyl intramembrane proteases are known to contribute to sequential processing of type II‐oriented membrane proteins referred to as regulated intramembrane proteolysis. The ER‐resident family members SPP and SPPL2c were shown to also cleave tail‐anchored proteins, including selected SNARE (soluble N‐ethylmaleimide‐sensitive factor attachment protein receptor) proteins facilitating membrane fusion events. Here, we analysed whether the related SPPL2a and SPPL2b proteases, which localise to the endocytic or late secretory pathway, are also able to process SNARE proteins. Therefore, we screened 18 SNARE proteins for cleavage by SPPL2a and SPPL2b based on cellular co‐expression assays, of which the proteins VAMP1, VAMP2, VAMP3 and VAMP4 were processed by SPPL2a/b demonstrating the capability of these two proteases to proteolyse tail‐anchored proteins. Cleavage of the four SNARE proteins was scrutinised at the endogenous level upon SPPL2a/b inhibition in different cell lines as well as by analysing VAMP1‐4 levels in tissues and primary cells of SPPL2a/b double‐deficient (dKO) mice. Loss of SPPL2a/b activity resulted in an accumulation of VAMP1‐4 in a cell type‐ and tissue‐dependent manner, identifying these proteins as SPPL2a/b substrates validated in vivo. Therefore, we propose that SPPL2a/b control cellular levels of VAMP1‐4 by initiating the degradation of these proteins, which might impact cellular trafficking.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 90%

The intramembrane proteases SPPL2a and SPPL2b regulate the homeostasis of selected SNARE proteins

et al. 2022

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“…Although this does not fully exclude binding of Frey to potential exosites on the enzyme required for substrate recruitment, these data are suggestive of a model in which Frey specifically interacts with the catalytic center of SPPL2c with high affinity, thereby blocking access of potential substrate molecules. How this high affinity can be obtained and whether an inhibitory motif within the Frey TMD might contribute to this will be a central question of further research, especially since analysis of cleavage sites of aspartic intramembrane proteases has not revealed any obvious consensus cleavage sites yet (21,23,30). Stabilization of Frey by SPPL2c represents the first described nonproteolytic function of an SPPL2c protease.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, the contribution of the intramembrane-cleaving protease (I-CLiP) signal peptide peptidase-like 2c (SPPL2c) to regulation of male fertility has been demonstrated. SPPL2c is a nine–transmembrane domain (TMD) aspartic protease that is highly expressed in the spermatid stage of male germ cells but absent from mature spermatozoa ( 20 , 21 ). In contrast to the closely related γ-secretase that acts on a multitude of substrate molecules in a rather promiscuous way ( 22 , 23 ), mass spectrometric analysis of testis membranes of wild-type or SPPL2c-deficient mice only revealed two physiological substrates of SPPL2c: phospholamban (PLN) that is involved in regulation of endoplasmic reticulum (ER)–resident calcium pumps and the SNAP Receptor (SNARE)-molecule Syntaxin8 (Stx8).…”

Section: Introductionmentioning

confidence: 99%

C11orf94/Frey is a key regulator for male fertility by controlling Izumo1 complex assembly

et al. 2022

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Although gamete fusion represents the central event in sexual reproduction, the required protein machinery is poorly defined. In sperm cells, Izumo1 and several Izumo1-associated proteins play an essential role for this process. However, so far, the mechanisms underlying transport and maturation of Izumo1 and its incorporation into high molecular weight complexes are incompletely defined. Here, we provide a detailed characterization of the C11orf94 protein, which we rename Frey, which provides a platform for the assembly of Izumo1 complexes. By retaining Izumo1 in the endoplasmic reticulum, Frey facilitates its incorporation into high molecular weight complexes. To fulfill its function, the unstable Frey protein is stabilized within the catalytic center of an intramembrane protease. Loss of Frey results in reduced assembly of Izumo1 complexes and male infertility due to impaired gamete fusion. Collectively, these findings provide mechanistic insights into the early biogenesis and functional relevance of Izumo1 complexes.

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“…The table below shows representative compounds tested for Sppl2a inhibition and the biological data obtained from testing representative examples. …”

Section: Important Compound Classesmentioning

confidence: 99%

Diazepinone Compounds as Sppl2a Inhibitors for Treating Autoimmune Diseases and Lymphomas

Sabnis¹

2022

ACS Med. Chem. Lett.

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Assignee Company. Novartis AG, Switzerland Disease Area. Autoimmune diseases and lymphomas Biological Target. Sppl2a Summary. The protein signal peptide peptidase-like protease 2a (Sppl2a) appears to play a role in innate and adaptive immunity by cleaving different transmembraneanchored proteins and thereby affecting the function of a variety of immune cells. Sppl2a was initially described as the protease cleaving the membrane-spanning portion of TNF-α and thereby controlling the release of IL-12 from dendritic cells. Inhibition of this protease may be relevant for the repression of detrimental, uncontrolled immune responses, e.g., pathological conditions where autoantibodies might be critical to autoimmune diseases. Sppl2a inhibition might influence the proliferation of B-cell lymphomas.The present application describes a series of novel diazepinone compounds as Sppl2a inhibitors for the treatment of autoimmune diseases and lymphomas. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.

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Signal peptide peptidase-like 2 proteases: Regulatory switches or proteasome of the membrane?

Cited by 7 publications

References 111 publications

The intramembrane proteases SPPL2a and SPPL2b regulate the homeostasis of selected SNARE proteins

The intramembrane proteases SPPL2a and SPPL2b regulate the homeostasis of selected SNARE proteins

C11orf94/Frey is a key regulator for male fertility by controlling Izumo1 complex assembly

Diazepinone Compounds as Sppl2a Inhibitors for Treating Autoimmune Diseases and Lymphomas

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