Special Issue "Unconventional Protein Secretion in Development and Disease"

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (1 June 2019)

Special Issue Editor

Guest Editor
Dr. Bor Luen Tang

Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Website | E-Mail
Interests: membrane trafficking; neuronal death and regeneration; Sirt1 and aging

Special Issue Information

Dear Colleagues,

The constitutive or regulated secretory pathway characterized by vesicular traffic from the endoplasmic reticulum, through the Golgi apparatus and towards the plasma membrane has been long recognized for all eukaryotic cells. However, an increasing number of proteins are also found to be secreted in an unconventional manner, in modes that are insensitive to inhibitors of conventional exocytosis and/or use a routes that bypasses the Golgi apparatus. Prominent examples of these include the fibroblast growth factor 2 (FGF2) and interleukin-1β (IL-1β), and even membrane proteins such as integrin-alpha and the cystic fibrosis transmembrane conductor (CFTR). Unconventional secretion may be important for cellular homeostasis as well as waste clearance and in some instances secreted proteins are known to play roles in intercellular signalling. Cellular mechanisms underlying the multiple modes of unconventional protein secretion range from a recently deciphered form of plasma membrane translocation to processes involving the generation of secretory autophagosomes, secretory lysosomes, ectosomes, exosomes and other extracellular microvesicles. The mechanisms underlying processes are not yet fully known or understood and this is an active area of study in cell biology.

Importantly, unconventional protein secretion has been shown to play important roles during development, such as in the secretion of the transcription factor Engrailed and the cell adhesion molecule integrin-α. Unconventional secretion of pathological factors such as α-Synuclein, Tau, Huntingtin, TDP-43 and Superoxide dismutase 1 (SOD1) likely play significant roles in the pathological spread of important neurodegenerative diseases. Unconventional secretion is important for immune modulation and contributes to cancer cell/tissue secretomes. These unconventionally secreted proteins could have therefore have oncogenic roles and may be useful cancer biomarkers.

In this special issue of Cells, we invite your contributions, either in the form of original research articles, reviews, or shorter “Perspective” articles on all aspects related to the theme of “Unconventional Protein Secretion in Development and Disease”. Articles with mechanistic and functional insights from a cell and molecular biological perspective are particularly welcome. Relevant topics include, but are not limited to

  • Unconventional secretion of specific cargo molecules in mammalian and plant cells
  • Mechanisms of unconventional secretion in eukaryotes
  • Unconventional secretion during embryonic development
  • Unconventional secretion in immune function and diseases
  • Unconventional secretion in cancer
  • Unconventional secretion in neurodegenerative diseases
Assoc. Prof. Bor Luen Tang
Guest Editor

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Keywords

  • α-Synuclein
  • autophagy
  • FGF2
  • IL-1β
  • microvesicles
  • Tau
  • unconventional secretion

Published Papers (4 papers)

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Research

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Open AccessArticle
Folding Status Is Determinant over Traffic-Competence in Defining CFTR Interactors in the Endoplasmic Reticulum
Received: 28 February 2019 / Revised: 9 April 2019 / Accepted: 12 April 2019 / Published: 14 April 2019
Cited by 1 | PDF Full-text (3157 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The most common cystic fibrosis-causing mutation (F508del, present in ~85% of CF patients) leads to CFTR misfolding, which is recognized by the endoplasmic reticulum (ER) quality control (ERQC), resulting in ER retention and early degradation. It is known that CFTR exit from the [...] Read more.
The most common cystic fibrosis-causing mutation (F508del, present in ~85% of CF patients) leads to CFTR misfolding, which is recognized by the endoplasmic reticulum (ER) quality control (ERQC), resulting in ER retention and early degradation. It is known that CFTR exit from the ER is mediated by specific retention/sorting signals that include four arginine-framed tripeptide (AFT) retention motifs and a diacidic (DAD) exit code that controls the interaction with the COPII machinery. Here, we aim at obtaining a global view of the protein interactors that regulate CFTR exit from the ER. We used mass spectrometry-based interaction proteomics and bioinformatics analyses to identify and characterize proteins interacting with selected CFTR peptide motifs or full-length CFTR variants retained or bypassing these ERQC checkpoints. We conclude that these ERQC trafficking checkpoints rely on fundamental players in the secretory pathway, detecting key components of the protein folding machinery associated with the AFT recognition and of the trafficking machinery recognizing the diacidic code. Furthermore, a greater similarity in terms of interacting proteins is observed for variants sharing the same folding defect over those reaching the same cellular location, evidencing that folding status is dominant over ER escape in shaping the CFTR interactome. Full article
(This article belongs to the Special Issue Unconventional Protein Secretion in Development and Disease)
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Review

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Open AccessFeature PaperReview
The Roles of Endo-Lysosomes in Unconventional Protein Secretion
Cells 2018, 7(11), 198; https://doi.org/10.3390/cells7110198
Received: 6 October 2018 / Revised: 30 October 2018 / Accepted: 31 October 2018 / Published: 3 November 2018
PDF Full-text (972 KB) | HTML Full-text | XML Full-text
Abstract
Protein secretion in general depends on signal sequence (also named leader sequence), a hydrophobic segment located at or close to the NH2-terminus of a secretory or membrane protein. This sequence guides the entry of nascent polypeptides into the lumen or membranes of the [...] Read more.
Protein secretion in general depends on signal sequence (also named leader sequence), a hydrophobic segment located at or close to the NH2-terminus of a secretory or membrane protein. This sequence guides the entry of nascent polypeptides into the lumen or membranes of the endoplasmic reticulum (ER) for folding, assembly, and export. However, evidence accumulated in recent years has suggested the existence of a collection of unconventional protein secretion (UPS) mechanisms that are independent of the canonical vesicular trafficking route between the ER and the plasma membrane (PM). These UPS mechanisms export soluble proteins bearing no signal sequence. The list of UPS cargos is rapidly expanding, along with the implicated biological functions, but molecular mechanisms accountable for the secretion of leaderless proteins are still poorly defined. This review summarizes our current understanding of UPS mechanisms with an emphasis on the emerging role of endo-lysosomes in this process. Full article
(This article belongs to the Special Issue Unconventional Protein Secretion in Development and Disease)
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Open AccessFeature PaperReview
Evaluation of Unconventional Protein Secretion by Saccharomyces cerevisiae and other Fungi
Received: 31 July 2018 / Revised: 27 August 2018 / Accepted: 27 August 2018 / Published: 31 August 2018
Cited by 2 | PDF Full-text (560 KB) | HTML Full-text | XML Full-text
Abstract
Development of proteome analysis of extracellular proteins has revealed that a wide variety of proteins, including fungal allergens are present outside the cell. These secreted allergens often do not contain known secretion signal sequences. Recent research progress shows that some fungal allergens are [...] Read more.
Development of proteome analysis of extracellular proteins has revealed that a wide variety of proteins, including fungal allergens are present outside the cell. These secreted allergens often do not contain known secretion signal sequences. Recent research progress shows that some fungal allergens are secreted by unconventional secretion pathways, including autophagy- and extracellular-vesicle-dependent pathways. However, secretion pathways remain unknown for the majority of extracellular proteins. This review summarizes recent data on unconventional protein secretion in Saccharomyces cerevisiae and other fungi. Particularly, methods for evaluating unconventional protein secretion are proposed for fungal species, including S. cerevisiae, a popular model organism for investigating protein secretion pathways. Full article
(This article belongs to the Special Issue Unconventional Protein Secretion in Development and Disease)
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Open AccessFeature PaperReview
Unconventional Secretion and Intercellular Transfer of Mutant Huntingtin
Received: 23 May 2018 / Revised: 8 June 2018 / Accepted: 12 June 2018 / Published: 14 June 2018
Cited by 1 | PDF Full-text (754 KB) | HTML Full-text | XML Full-text
Abstract
The mechanism of intercellular transmission of pathological agents in neurodegenerative diseases has received much recent attention. Huntington’s disease (HD) is caused by a monogenic mutation in the gene encoding Huntingtin (HTT). Mutant HTT (mHTT) harbors a CAG repeat extension which encodes an abnormally [...] Read more.
The mechanism of intercellular transmission of pathological agents in neurodegenerative diseases has received much recent attention. Huntington’s disease (HD) is caused by a monogenic mutation in the gene encoding Huntingtin (HTT). Mutant HTT (mHTT) harbors a CAG repeat extension which encodes an abnormally long polyglutamine (polyQ) repeat at HTT’s N-terminus. Neuronal pathology in HD is largely due to the toxic gain-of-function by mHTT and its proteolytic products, which forms both nuclear and cytoplasmic aggregates that perturb nuclear gene transcription, RNA splicing and transport as well cellular membrane dynamics. The neuropathological effects of mHTT have been conventionally thought to be cell-autonomous in nature. Recent findings have, however, indicated that mHTT could be secreted by neurons, or transmitted from one neuronal cell to another via different modes of unconventional secretion, as well as via tunneling nanotubes (TNTs). These modes of transmission allow the intercellular spread of mHTT and its aggregates, thus plausibly promoting neuropathology within proximal neuronal populations and between neurons that are connected within neural circuits. Here, the various possible modes for mHTT’s neuronal cell exit and intercellular transmission are discussed. Full article
(This article belongs to the Special Issue Unconventional Protein Secretion in Development and Disease)
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