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Domain architecture of vasohibins required for their chaperone-dependent unconventional extracellular release.

ABSTRACT: Vasohibins (VASH1 and VASH2) are recently identified regulators of angiogenesis and cancer cell functions. They are secreted proteins without any classical secretion signal sequences, and are thought to be secreted instead via an unconventional protein secretion (UPS) pathway in a small vasohibin-binding protein (SVBP)-dependent manner. However, the precise mechanism of SVBP-dependent UPS is poorly understood. In this study, we identified a novel UPS regulatory system in which essential domain architecture (VASH-PS) of VASHs, comprising regions VASH191-180 and VASH280-169 , regulate the cytosolic punctate structure formation in the absence of SVBP. We also demonstrate that SVBP form a complex with VASH1 through the VASH1274-282 (SIa), VASH1139-144 (SIb), and VASH1133-137 (SIc), leading to the dispersion in the cytosol and extracellular release of VASH1. The amino acid sequences of VASH-SIa and VASH-PS, containing SIb and SIc, are highly conserved among VASH family members in vertebrates, suggesting that SVBP-dependent UPS may be common within the VASH family. This novel UPS regulatory system may open up new avenues for understanding fundamental protein secretion in vertebrates.

SUBMITTER: Kadonosono T

PROVIDER: S-EPMC5326560 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Domain architecture of vasohibins required for their chaperone-dependent unconventional extracellular release.

Kadonosono Tetsuya T Yimchuen Wanaporn W Tsubaki Takuya T Shiozawa Tadashi T Suzuki Yasuhiro Y Kuchimaru Takahiro T Sato Yasufumi Y Kizaka-Kondoh Shinae S

Protein science : a publication of the Protein Society 20170211 3

Vasohibins (VASH1 and VASH2) are recently identified regulators of angiogenesis and cancer cell functions. They are secreted proteins without any classical secretion signal sequences, and are thought to be secreted instead via an unconventional protein secretion (UPS) pathway in a small vasohibin-binding protein (SVBP)-dependent manner. However, the precise mechanism of SVBP-dependent UPS is poorly understood. In this study, we identified a novel UPS regulatory system in which essential domain a ...[more]

PMID: 27879017

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Project description:BackgroundThe multifunctional protein CD98 heavy chain (CD98hc, Slc3a2) associates with integrin ?1 through its cytoplasmic and transmembrane domains and the CD98hc-mediated integrin signaling is required for maintenance of ES cell proliferation. CD98hc-null mice exhibit early post-implantation lethality similar to integrin ?1-null mice, supporting the importance of its interaction with integrin ?1. On the other hand, the extracellular domain of CD98hc interacts with L-type amino acid transporters (LATs) and is essential for appropriate cell surface distribution of LATs. LATs mediate the transport of amino acids and other molecules such as thyroid hormone. In this respect, CD98hc may also affect development via these transporters.ResultsIn this study, mice were generated from embryonic stem (ES) cell line (PST080) harboring a mutant CD98hc allele (CD98hc?/+). Expression of the CD98hc mutant allele results in ?CD98hc-? geo fusion protein where extracellular C-terminal 102 amino acids of CD98hc are replaced with ? geo. Analyses of PST080 ES cells as well as reconstituted frog oocytes demonstrated that ?CD98hc-? geo fusion protein preserved its ability to interact with integrin ?1 although this mutant protein was hardly localized on the cell surface. These findings suggest that ?CD98hc-? geo protein can mediate integrin signaling but cannot support amino acid transport through LATs. CD98hc?/+ mice were normal. Although some of the implantation sites lacked embryonic component at E9.5, all the implantation sites contained embryonic component at E7.5. Thus, CD98hc?/? embryos are likely to die between E7.5 and E9.5.ConclusionsConsidering that CD98hc complete knockout (CD98hc-/-) embryos are reported to die shortly after implantation, our findings suggest potential stage-specific roles of CD98hc in murine embryonic development. CD98hc may be essential for early post-implantation development by regulating integrin-dependent signaling, while the other function of CD98hc as a component of amino acid transporters may be required for embryonic development at later stages.

Dataset Information

Domain architecture of vasohibins required for their chaperone-dependent unconventional extracellular release.

Publications

Domain architecture of vasohibins required for their chaperone-dependent unconventional extracellular release.

Similar Datasets

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