HAI-2 stabilizes, inhibits, and regulates SEA-cleavage-dependent secretory transport of matriptase

Annika W. Nonboe; Oliver Krigslund; Christoffer Soendergaard; Signe Skovbjerg; Stine Friis; Martin Nybo Andersen; Vincent Ellis; Makiko Kawaguchi; Hiroaki Kataoka; Thomas H. Bugge; Lotte K. Vogel

doi:10.1111/tra.12482

HAI-2 stabilizes, inhibits, and regulates SEA-cleavage-dependent secretory transport of matriptase

Annika W. Nonboe
, Oliver Krigslund
, Christoffer Soendergaard
, Signe Skovbjerg
, Stine Friis
, Martin Nybo Andersen
, Vincent Ellis
, Makiko Kawaguchi
, Hiroaki Kataoka
, Thomas H. Bugge
, Lotte K. Vogel

School of Biological Sciences

Research output: Contribution to journal › Article › peer-review

24 Citations (Scopus)

31 Downloads (Pure)

Abstract

It has recently been shown that HAI-2 is able to suppress carcinogenesis induced by overexpression of matriptase, as well as cause regression of individual established tumors in a mouse model system. However, the role of HAI-2 is poorly understood.

In the present study we describe three mutations in the binding loop of the HAI-2 Kunitz domain 1 (K42N, C47F, and R48L) that cause a delay in the SEA domain cleavage of matriptase, leading to accumulation of non-SEA domain cleaved matriptase in the ER.

We suggest that, like other known SEA domains, the matriptase SEA domain auto-cleaves and reflects that correct oligomerization, maturation, and/or folding has been obtained. Our results suggest that the HAI-2 Kunitz domain 1 mutants influence the flux of matriptase to the plasma membrane by affecting the oligomerization, maturation, and/or folding of matriptase, and as a result the SEA domain cleavage of matriptase.

Two of the HAI-2 Kunitz domain 1 mutants investigated (C47F, R48L, C47F/R48L) also displayed a reduced ability to proteolytically silence matriptase. Hence, HAI-2 separately stabilizes matriptase, regulates the secretory transport, possibly via maturation/oligomerization, and inhibits the proteolytic activity of matriptase in the ER, and possible throughout the secretory pathway.

Original language	English
Pages (from-to)	378–391
Number of pages	14
Journal	Traffic
Volume	18
Issue number	6
Early online date	28 Mar 2017
DOIs	https://doi.org/10.1111/tra.12482
Publication status	Published - Jun 2017

Keywords

matriptase
HAI-2
HAI-1
SEA domain cleavage
secretory transport
chromogenic activity

Access to Document

10.1111/tra.12482

Accepted manuscriptAccepted author manuscript, 1.9 MB

http://doi.wiley.com/10.1111/tra.12482

Cite this

@article{b80d190e17574a89b09d91830600c5c7,

title = "HAI-2 stabilizes, inhibits, and regulates SEA-cleavage-dependent secretory transport of matriptase",

abstract = "It has recently been shown that HAI-2 is able to suppress carcinogenesis induced by overexpression of matriptase, as well as cause regression of individual established tumors in a mouse model system. However, the role of HAI-2 is poorly understood. In the present study we describe three mutations in the binding loop of the HAI-2 Kunitz domain 1 (K42N, C47F, and R48L) that cause a delay in the SEA domain cleavage of matriptase, leading to accumulation of non-SEA domain cleaved matriptase in the ER. We suggest that, like other known SEA domains, the matriptase SEA domain auto-cleaves and reflects that correct oligomerization, maturation, and/or folding has been obtained. Our results suggest that the HAI-2 Kunitz domain 1 mutants influence the flux of matriptase to the plasma membrane by affecting the oligomerization, maturation, and/or folding of matriptase, and as a result the SEA domain cleavage of matriptase. Two of the HAI-2 Kunitz domain 1 mutants investigated (C47F, R48L, C47F/R48L) also displayed a reduced ability to proteolytically silence matriptase. Hence, HAI-2 separately stabilizes matriptase, regulates the secretory transport, possibly via maturation/oligomerization, and inhibits the proteolytic activity of matriptase in the ER, and possible throughout the secretory pathway.",

keywords = "matriptase, HAI-2, HAI-1, SEA domain cleavage, secretory transport, chromogenic activity",

author = "Nonboe, \{Annika W.\} and Oliver Krigslund and Christoffer Soendergaard and Signe Skovbjerg and Stine Friis and Andersen, \{Martin Nybo\} and Vincent Ellis and Makiko Kawaguchi and Hiroaki Kataoka and Bugge, \{Thomas H.\} and Vogel, \{Lotte K.\}",

year = "2017",

month = jun,

doi = "10.1111/tra.12482",

language = "English",

volume = "18",

pages = "378–391",

journal = "Traffic",

issn = "1398-9219",

publisher = "Wiley",

number = "6",

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T1 - HAI-2 stabilizes, inhibits, and regulates SEA-cleavage-dependent secretory transport of matriptase

AU - Nonboe, Annika W.

AU - Krigslund, Oliver

AU - Soendergaard, Christoffer

AU - Skovbjerg, Signe

AU - Friis, Stine

AU - Andersen, Martin Nybo

AU - Ellis, Vincent

AU - Kawaguchi, Makiko

AU - Kataoka, Hiroaki

AU - Bugge, Thomas H.

AU - Vogel, Lotte K.

PY - 2017/6

Y1 - 2017/6

N2 - It has recently been shown that HAI-2 is able to suppress carcinogenesis induced by overexpression of matriptase, as well as cause regression of individual established tumors in a mouse model system. However, the role of HAI-2 is poorly understood. In the present study we describe three mutations in the binding loop of the HAI-2 Kunitz domain 1 (K42N, C47F, and R48L) that cause a delay in the SEA domain cleavage of matriptase, leading to accumulation of non-SEA domain cleaved matriptase in the ER. We suggest that, like other known SEA domains, the matriptase SEA domain auto-cleaves and reflects that correct oligomerization, maturation, and/or folding has been obtained. Our results suggest that the HAI-2 Kunitz domain 1 mutants influence the flux of matriptase to the plasma membrane by affecting the oligomerization, maturation, and/or folding of matriptase, and as a result the SEA domain cleavage of matriptase. Two of the HAI-2 Kunitz domain 1 mutants investigated (C47F, R48L, C47F/R48L) also displayed a reduced ability to proteolytically silence matriptase. Hence, HAI-2 separately stabilizes matriptase, regulates the secretory transport, possibly via maturation/oligomerization, and inhibits the proteolytic activity of matriptase in the ER, and possible throughout the secretory pathway.

AB - It has recently been shown that HAI-2 is able to suppress carcinogenesis induced by overexpression of matriptase, as well as cause regression of individual established tumors in a mouse model system. However, the role of HAI-2 is poorly understood. In the present study we describe three mutations in the binding loop of the HAI-2 Kunitz domain 1 (K42N, C47F, and R48L) that cause a delay in the SEA domain cleavage of matriptase, leading to accumulation of non-SEA domain cleaved matriptase in the ER. We suggest that, like other known SEA domains, the matriptase SEA domain auto-cleaves and reflects that correct oligomerization, maturation, and/or folding has been obtained. Our results suggest that the HAI-2 Kunitz domain 1 mutants influence the flux of matriptase to the plasma membrane by affecting the oligomerization, maturation, and/or folding of matriptase, and as a result the SEA domain cleavage of matriptase. Two of the HAI-2 Kunitz domain 1 mutants investigated (C47F, R48L, C47F/R48L) also displayed a reduced ability to proteolytically silence matriptase. Hence, HAI-2 separately stabilizes matriptase, regulates the secretory transport, possibly via maturation/oligomerization, and inhibits the proteolytic activity of matriptase in the ER, and possible throughout the secretory pathway.

KW - matriptase

KW - HAI-2

KW - HAI-1

KW - SEA domain cleavage

KW - secretory transport

KW - chromogenic activity

U2 - 10.1111/tra.12482

DO - 10.1111/tra.12482

M3 - Article

SN - 1398-9219

VL - 18

SP - 378

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JO - Traffic

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