MBTPS2, a membrane bound protease, underlying several distinct skin and bone disorders

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Abstract

The MBTPS2 gene on the X-chromosome encodes the membrane-bound transcription factor protease, site-2 (MBTPS2) or site-2 protease (S2P) which cleaves and activates several signaling and regulatory proteins from the membrane. The MBTPS2 is critical for a myriad of cellular processes, ranging from the regulation of cholesterol homeostasis to unfolded protein responses. While its functional role has become much clearer in the recent years, how mutations in the MBTPS2 gene lead to several human disorders with different phenotypes including Ichthyosis Follicularis, Atrichia and Photophobia syndrome (IFAP) with or without BRESHECK syndrome, Keratosis Follicularis Spinulosa Decalvans (KFSD), Olmsted syndrome, and Osteogenesis Imperfecta type XIX remains obscure. This review presents the biological role of MBTPS2 in development, summarizes its mutations and implicated disorders, and discusses outstanding unanswered questions.

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The EMBL-EBI search and sequence analysis tools APIs in 2019

Fábio Madeira, Young Park, Joon Lee … (2019)

Abstract The EMBL-EBI provides free access to popular bioinformatics sequence analysis applications as well as to a full-featured text search engine with powerful cross-referencing and data retrieval capabilities. Access to these services is provided via user-friendly web interfaces and via established RESTful and SOAP Web Services APIs (https://www.ebi.ac.uk/seqdb/confluence/display/JDSAT/EMBL-EBI+Web+Services+APIs+-+Data+Retrieval). Both systems have been developed with the same core principles that allow them to integrate an ever-increasing volume of biological data, making them an integral part of many popular data resources provided at the EMBL-EBI. Here, we describe the latest improvements made to the frameworks which enhance the interconnectivity between public EMBL-EBI resources and ultimately enhance biological data discoverability, accessibility, interoperability and reusability.

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ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs.

Jin Ye, Robert Rawson, Ryutaro Komuro … (2000)

ATF6 is a membrane-bound transcription factor that activates genes in the endoplasmic reticulum (ER) stress response. When unfolded proteins accumulate in the ER, ATF6 is cleaved to release its cytoplasmic domain, which enters the nucleus. Here, we show that ATF6 is processed by Site-1 protease (S1P) and Site-2 protease (S2P), the enzymes that process SREBPs in response to cholesterol deprivation. ATF6 processing was blocked completely in cells lacking S2P and partially in cells lacking S1P. ATF6 processing required the RxxL and asparagine/proline motifs, known requirements for S1P and S2P processing, respectively. Cells lacking S2P failed to induce GRP78, an ATF6 target, in response to ER stress. ATF6 processing did not require SCAP, which is essential for SREBP processing. We conclude that S1P and S2P are required for the ER stress response as well as for lipid synthesis.

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ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfolded protein response.

H Yoshida, T. Okada, K Haze … (2000)

Transcription of genes encoding molecular chaperones and folding enzymes in the endoplasmic reticulum (ER) is induced by accumulation of unfolded proteins in the ER. This intracellular signaling, known as the unfolded protein response (UPR), is mediated by the cis-acting ER stress response element (ERSE) in mammals. In addition to ER chaperones, the mammalian transcription factor CHOP (also called GADD153) is induced by ER stress. We report here that the transcription factor XBP-1 (also called TREB5) is also induced by ER stress and that induction of CHOP and XBP-1 is mediated by ERSE. The ERSE consensus sequence is CCAAT-N(9)-CCACG. As the general transcription factor NF-Y (also known as CBF) binds to CCAAT, CCACG is considered to provide specificity in the mammalian UPR. We recently found that the basic leucine zipper protein ATF6 isolated as a CCACG-binding protein is synthesized as a transmembrane protein in the ER, and ER stress-induced proteolysis produces a soluble form of ATF6 that translocates into the nucleus. We report here that overexpression of soluble ATF6 activates transcription of the CHOP and XBP-1 genes as well as of ER chaperone genes constitutively, whereas overexpression of a dominant negative mutant of ATF6 blocks the induction by ER stress. Furthermore, we demonstrated that soluble ATF6 binds directly to CCACG only when CCAAT exactly 9 bp upstream of CCACG is bound to NF-Y. Based on these and other findings, we concluded that specific and direct interactions between ATF6 and ERSE are critical for transcriptional induction not only of ER chaperones but also of CHOP and XBP-1.

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Author and article information

Contributors

Thantrira Porntaveetus:

ORCID: http://orcid.org/0000-0003-0145-9801

thantrira.p@chula.ac.th

Journal

Journal ID (nlm-ta): J Transl Med

Journal ID (iso-abbrev): J Transl Med

Title: Journal of Translational Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1479-5876

Publication date (Electronic): 20 March 2021

Publication date PMC-release: 20 March 2021

Publication date Collection: 2021

Volume: 19

Electronic Location Identifier: 114

Affiliations

[1 ]GRID grid.7922.e, ISNI 0000 0001 0244 7875, Center of Excellence for Medical Genomics, Medical Genomics Cluster, Department of Pediatrics, Faculty of Medicine, , Chulalongkorn University, ; Bangkok, 10330 Thailand

[2 ]Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, 10330 Thailand

[3 ]GRID grid.7922.e, ISNI 0000 0001 0244 7875, Genomics and Precision Dentistry Research Unit, Department of Physiology, Faculty of Dentistry, , Chulalongkorn University, ; Bangkok, 10330 Thailand

Author information

Thantrira Porntaveetus http://orcid.org/0000-0003-0145-9801

Article

Publisher ID: 2779

DOI: 10.1186/s12967-021-02779-5

PMC ID: 7981912

PubMed ID: 33743732

SO-VID: ef6037a1-7ead-4927-b9d0-a2225ad69529

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 16 January 2021

Date accepted : 8 March 2021

Funding

Funded by: National Research Council of Thailand

Funded by: TSRI fund

Award ID: CU_FRB640001_01_32_3, CU_FRB640001_01_32_4

Award Recipient : Thantrira Porntaveetus

Funded by: Global partnership

Award ID: CU-C16F630029

Award Recipient : Thantrira Porntaveetus

Funded by: Health Systems Research Institute

Funded by: FundRef http://dx.doi.org/10.13039/501100004396, Thailand Research Fund;

Award ID: MRG6280001

Award ID: DPG6180001

Award Recipient : Thantrira Porntaveetus Vorasuk Shotelersuk

Funded by: Faculty Research Grant, Faculty of Dentistry, Chulalongkorn University

Award ID: DRF64013

Award Recipient : Thantrira Porntaveetus

Funded by: Ratchadapisek Somphot Fund for Postdoctoral Fellowship, Chulalongkorn University

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ScienceOpen disciplines: Medicine

Keywords: bresheck,kfsd,ifap,olmsted syndrome,osteogenesis imperfecta,s2p

Data availability:

ScienceOpen disciplines: Medicine

Keywords: bresheck, kfsd, ifap, olmsted syndrome, osteogenesis imperfecta, s2p

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MBTPS2, a membrane bound protease, underlying several distinct skin and bone disorders

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Karger: Dermatology

Most cited references 126

The EMBL-EBI search and sequence analysis tools APIs in 2019

ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs.

ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfolded protein response.

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