Regulation of ADAM10 by the TspanC8 Family of Tetraspanins and Their Therapeutic Potential

Harrison, Neale; Koo, Chek Ziu; Tomlinson, Michael G.

doi:10.3390/ijms22136707

“…The identification of additional proteins trafficked by TSP-12 and TSP-14 (either TSP-14A or TSP-14B or both), and subsequent determination on how TSP-12 and TSP-14 regulate their trafficking/localization will elucidate how these two tetraspanin proteins function during the development of a multicellular living organism like C. elegans. The information obtained could shed light on the myriad of complex functions of the various TspanC8 proteins in mammals, and ultimately aid in the development of therapeutic strategies for the treatment of various diseases caused by abnormal expression or function of certain tetraspanins [33][34][35].…”

Section: Discussionmentioning

confidence: 99%

The C. elegans TspanC8 tetraspanin TSP-14 exhibits isoform-specific localization and function

Liu

¹

,

Shi

²

,

Liu

³

2022

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Tetraspanin proteins are a unique family of highly conserved four-pass transmembrane proteins in metazoans. While much is known about their biochemical properties, the in vivo functions and distribution patterns of different tetraspanin proteins are less understood. Previous studies have shown that two paralogous tetraspanins that belong to the TspanC8 subfamily, TSP-12 and TSP-14, function redundantly to promote both Notch signaling and bone morphogenetic protein (BMP) signaling in C. elegans. TSP-14 has two isoforms, TSP-14A and TSP-14B, where TSP-14B has an additional 24 amino acids at its N-terminus compared to TSP-14A. By generating isoform specific knock-ins and knock-outs using CRISPR, we found that TSP-14A and TSP-14B share distinct as well as overlapping expression patterns and functions. While TSP-14A functions redundantly with TSP-12 to regulate body size and embryonic and vulva development, TSP-14B primarily functions redundantly with TSP-12 to regulate postembryonic mesoderm development. Importantly, TSP-14A and TSP-14B exhibit distinct subcellular localization patterns. TSP-14A is localized apically and on early and late endosomes. TSP-14B is localized to the basolateral cell membrane. We further identified a di-leucine motif within the N-terminal 24 amino acids of TSP-14B that serves as a basolateral membrane targeting sequence, and showed that the basolateral membrane localization of TSP-14B is important for its function. Our work highlights the diverse and intricate functions of TspanC8 tetraspanins in C. elegans, and demonstrates the importance of dissecting the functions of these important proteins in an intact living organism.

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“…The identification of additional proteins trafficked by TSP-12 and TSP-14 (either TSP-14A or TSP-14B or both), and subsequent determination on how TSP-12 and TSP-14 regulate their trafficking/localization will elucidate how these two tetraspanin proteins function during the development of a multicellular living organism like C. elegans. The information obtained could shed light on the myriad of complex functions of the various TspanC8 proteins in mammals, and ultimately aid in the development of therapeutic strategies for the treatment of various diseases caused by abnormal expression or function of certain tetraspanins [32][33][34].…”

Section: Liu Et Almentioning

confidence: 99%

The C. elegans TspanC8 tetraspanin TSP-14 exhibits isoform-specific localization and function

Liu

¹

,

Shi

²

,

Li

³

2021

Preprint

0

View full text Add to dashboard Cite

Tetraspanin proteins are a unique family of highly conserved four-pass transmembrane proteins in metazoans. While much is known about their biochemical properties, the in vivo functions and distribution patterns of different tetraspanin proteins are less understood. Previous studies have shown that two paralogous tetraspanins that belong to the TspanC8 subfamily, TSP-12 and TSP-14, function redundantly to promote both Notch signaling and bone morphogenetic protein (BMP) signaling in C. elegans. TSP-14 has two isoforms, TSP-14A and TSP-14B, where TSP-14B has an additional 24 amino acids at its N-terminus compared to TSP-14A. By generating isoform specific knock-ins and knock-outs using CRISPR, we found that TSP-14A and TSP-14B share distinct as well as overlapping expression patterns and functions. While TSP-14A functions redundantly with TSP-12 to regulate body size and embryonic and vulva development, TSP-14B primarily functions redundantly with TSP-12 to regulate postembryonic mesoderm development. Importantly, TSP-14A and TSP-14B exhibit distinct subcellular localization patterns. TSP-14A is localized apically and on early and late endosomes. TSP-14B is localized to the basolateral cell membrane. We further identified a di-leucine motif within the N-terminal 24 amino acids of TSP-14B that serves as a basolateral membrane targeting sequence, and showed that the basolateral membrane localization of TSP-14B is important for its function. Our work highlights the diverse and intricate functions of TspanC8 tetraspanins in C. elegans, and demonstrates the importance of dissecting the functions of these important proteins in an intact living organism.Author summaryTetraspanin proteins are a unique family of highly conserved four-pass transmembrane proteins in higher eukaryotes. Abnormal expression of certain tetraspanins is associated with various types of diseases, including cancer. Understanding the functions of different tetraspanin proteins in vivo is crucial in deciphering the link between tetraspanins and their associated disease states. We have previously identified two tetraspanins, TSP-12 and TSP-14, that share redundant functions in regulating multiple aspects of C. elegans development. Here we show that TSP-14 has two protein isoforms. Using CRISPR knock-in and knock-out technology, we have found that the two isoforms share unique, as well as overlapping expression patterns and functions. Furthermore, they exhibit distinct subcellular localization patterns. Our work highlights the diverse and intricate functions of tetraspanin proteins in a living multicellular organism, and demonstrates that protein isoforms are another mechanism C. elegans uses to increase the diversity and versatility of its proteome.

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“…A disintegrin and metalloproteinase 10 (ADAM10) is a ubiquitously expressed cell membrane-localized metalloproteinase, which cleaves the extracellular regions from its transmembrane protein substrates [ 7 ]. ADAM10 is the critical scissor and activator for Notch cell fate regulatory proteins, since genetic ablation of mouse ADAM10 is embryonically lethal due to impaired Notch signalling.…”

Section: Introductionmentioning

confidence: 99%

The Platelet Collagen Receptor GPVI Is Cleaved by Tspan15/ADAM10 and Tspan33/ADAM10 Molecular Scissors

Koo

¹

,

Matthews

²

,

Harrison

³

et al. 2022

IJMS

Self Cite

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The platelet-activating collagen receptor GPVI represents the focus of clinical trials as an antiplatelet target for arterial thrombosis, and soluble GPVI is a plasma biomarker for several human diseases. A disintegrin and metalloproteinase 10 (ADAM10) acts as a ‘molecular scissor’ that cleaves the extracellular region from GPVI and many other substrates. ADAM10 interacts with six regulatory tetraspanin membrane proteins, Tspan5, Tspan10, Tspan14, Tspan15, Tspan17 and Tspan33, which are collectively termed the TspanC8s. These are emerging as regulators of ADAM10 substrate specificity. Human platelets express Tspan14, Tspan15 and Tspan33, but which of these regulates GPVI cleavage remains unknown. To address this, CRISPR/Cas9 knockout human cell lines were generated to show that Tspan15 and Tspan33 enact compensatory roles in GPVI cleavage, with Tspan15 bearing the more important role. To investigate this mechanism, a series of Tspan15 and GPVI mutant expression constructs were designed. The Tspan15 extracellular region was found to be critical in promoting GPVI cleavage, and appeared to achieve this by enabling ADAM10 to access the cleavage site at a particular distance above the membrane. These findings bear implications for the regulation of cleavage of other ADAM10 substrates, and provide new insights into post-translational regulation of the clinically relevant GPVI protein.

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Regulation of ADAM10 by the TspanC8 Family of Tetraspanins and Their Therapeutic Potential

Cited by 30 publications

References 85 publications

The C. elegans TspanC8 tetraspanin TSP-14 exhibits isoform-specific localization and function

The C. elegans TspanC8 tetraspanin TSP-14 exhibits isoform-specific localization and function

The C. elegans TspanC8 tetraspanin TSP-14 exhibits isoform-specific localization and function

The Platelet Collagen Receptor GPVI Is Cleaved by Tspan15/ADAM10 and Tspan33/ADAM10 Molecular Scissors

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