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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (28 February 2017) | Viewed by 116383

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Prof. Dr. Gian-Pietro Di Sansebastiano

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Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, 73100 Lecce, LE, Italy
Interests: endomembrane trafficking; unconventional routes; metabolites and xenobiotics compartmentalization; biostimulation
Special Issues, Collections and Topics in MDPI journals

Dr. Antonio Gaballo

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Institute of Nanotechnology, CNR (CNR-Nanotec), Campus ECOTEKNE, 73100 Lecce, Italy
Interests: 3D cell cancer models; oxidative cell metabolism; tumor microenvironment

Special Issue Information

Dear Colleagues,

Eukaryotic cells have an extensive and highly dynamic internal membrane system. Beyond the well-established mechanism of protein transport through the Golgi and endosome derived vesicles, several “non classical” membrane trafficking and protein transport mechanisms, with critical physiological functions are becoming apparent. These diverse and heterogeneous mechanisms are collectively named “unconventional protein secretion” and include trafficking to and from the plasma membrane, transport processes between organelles, as well as intercellular communication (between cells).

The impact of unconventional secretion on human pathologies (tumorigenesis, neurodegenerative diseases, inflammation and tissue remodeling) and plant stress and development is considerable. An expanded study to all cellular models appears desirable to discover the general mechanisms regulating structural characteristics of these traffic events.

This Special Issue of the International Journal of Molecular Sciences (IJMS) is inspired by the forthcoming independent meeting “Unconventional Proteins and Membranes Traffic” (http://www.upmt.net) and aims to collect articles and reviews to provide a comprehensive overview of this fundamental area of biological and medical research to improve our understanding of eukaryotic cellular processes, pathogenicity and for the development of new biotechnological applications.

The current Special Issue is open to submissions of previously unpublished experimental, prospective, extended articles and review papers on the following and related topics:

Unconventional Proteins and Membranes Traffic
Endo-lysosomal/vacuolar system
Host-pathogen interactions through membranes
Extracellular vesicles

Prof. Dr. Gian-Pietro Di Sansebastian
Dr. Antonio Gaballo
Guest Editors

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Published Papers (11 papers)

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Research

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3538 KiB

Open AccessArticle

Applying Unconventional Secretion in Ustilago maydis for the Export of Functional Nanobodies

by Marius Terfrüchte, Michèle Reindl, Silke Jankowski, Parveen Sarkari, Michael Feldbrügge and Kerstin Schipper

Int. J. Mol. Sci. 2017, 18(5), 937; https://doi.org/10.3390/ijms18050937 - 29 Apr 2017

Cited by 20 | Viewed by 7012

Abstract

Exploiting secretory pathways for production of heterologous proteins is highly advantageous with respect to efficient downstream processing. In eukaryotic systems the vast majority of heterologous proteins for biotechnological application is exported via the canonical endoplasmic reticulum–Golgi pathway. In the endomembrane system target proteins are often glycosylated and may thus be modified with foreign glycan patterns. This can be destructive for their activity or cause immune reactions against therapeutic proteins. Hence, using unconventional secretion for protein expression is an attractive alternative. In the fungal model Ustilago maydis, chitinase Cts1 is secreted via an unconventional pathway connected to cell separation which can be used to co-export heterologous proteins. Here, we apply this mechanism for the production of nanobodies. First, we achieved expression and unconventional secretion of a functional nanobody directed against green fluorescent protein (Gfp). Second, we found that Cts1 binds to chitin and that this feature can be applied to generate a Gfp-trap. Thus, we demonstrated the dual use of Cts1 serving both as export vehicle and as purification tag. Finally, we established and optimized the production of a nanobody against botulinum toxin A and hence describe the first pharmaceutically relevant target exported by Cts1-mediated unconventional secretion. Full article

(This article belongs to the Special Issue Unconventional Proteins and Membranes Traffic)

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9056 KiB

Open AccessArticle

Subcellular Localization of Arabidopsis Pathogenesis-Related 1 (PR1) Protein

by Tamara Pečenková, Roman Pleskot and Viktor Žárský

Int. J. Mol. Sci. 2017, 18(4), 825; https://doi.org/10.3390/ijms18040825 - 13 Apr 2017

Cited by 50 | Viewed by 13087

Abstract

The Arabidopsis thaliana pathogenesis-related 1 (PR1) is an important defense protein, so far it has only been detected in extracellular space and its subcellular sorting and transport remain unexplained. Using a green fluorescent protein (GFP) tagged full length, as well as a C-terminus truncated version of PR1, we observed that when expressed ectopically in Nicotiana benthamiana leaves, PR1 co-localizes only partially with Golgi markers, and much more prominently with the late endosome (LE)/multivesicular body (MVB) FYVE marker. The C-truncated version PR1ΔC predominantly localized to the endoplasmic reticulum (ER). The same localizations were found for stable Arabidopsis transformants with expression of PR1 and PR1ΔC driven by the native promoter. We conclude that the A. thaliana PR1 (AtPR1) undergoes an unconventional secretion pathway, starting from the C-terminus-dependent sorting from the ER, and utilizing further transportation via phosphatidyl-inositol-3-phosphate (PI(3)P) positive LE/MVB-like vesicles. The homology model of the PR1 structure shows that the cluster of positively charged amino acid residues (arginines 60, 67, 137, and lysine 135) could indeed interact with negatively charged phospholipids of cellular membranes. It remains to be resolved whether Golgi and LE/MVB localization reflects an alternative sorting or trafficking succession, and what the role of lipid interactions in it will be. Full article

(This article belongs to the Special Issue Unconventional Proteins and Membranes Traffic)

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3507 KiB

Open AccessArticle

Arabidopsis RabF1 (ARA6) Is Involved in Salt Stress and Dark-Induced Senescence (DIS)

by Congfei Yin, Sazzad Karim, Hongsheng Zhang and Henrik Aronsson

Int. J. Mol. Sci. 2017, 18(2), 309; https://doi.org/10.3390/ijms18020309 - 1 Feb 2017

Cited by 17 | Viewed by 7231

Abstract

Arabidopsis small GTPase RabF1 (ARA6) functions in endosomal vesicle transport and may play a crucial role in recycling and degradation of molecules, thus involved in stress responses. Here we have reported that complementary overexpression lines RabF1OE (overexpression), GTPase mutants RabF1Q93L (constitutively active) and RabF1S47N (dominant negative) lines show longer root growth than wild-type, rabF1 knockout and N-myristoylation deletion (Δ1−29, N-terminus) complementary overexpression mutant plants under salt induced stress, which indicates that N-myristoylation of RabF1 is indispensable for salt tolerance. Moreover, RabF1 is highly expressed during senescence and RabF1OE lines were more tolerant of dark-induced senescence (DIS) than wild-type and rabF1. Full article

(This article belongs to the Special Issue Unconventional Proteins and Membranes Traffic)

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4494 KiB

Open AccessArticle

Dimerization of the Vacuolar Receptors AtRMR1 and -2 from Arabidopsis thaliana Contributes to Their Localization in the trans-Golgi Network

by Alessandro Occhialini, Guillaume Gouzerh, Gian-Pietro Di Sansebastiano and Jean-Marc Neuhaus

Int. J. Mol. Sci. 2016, 17(10), 1661; https://doi.org/10.3390/ijms17101661 - 30 Sep 2016

Cited by 17 | Viewed by 8090

Abstract

In Arabidopsis thaliana, different types of vacuolar receptors were discovered. The AtVSR (Vacuolar Sorting Receptor) receptors are well known to be involved in the traffic to lytic vacuole (LV), while few evidences demonstrate the involvement of the receptors from AtRMR family (Receptor Membrane RING-H2) in the traffic to the protein storage vacuole (PSV). In this study we focused on the localization of two members of AtRMR family, AtRMR1 and -2, and on the possible interaction between these two receptors in the plant secretory pathway. Our experiments with agroinfiltrated Nicotiana benthamiana leaves demonstrated that AtRMR1 was localized in the endoplasmic reticulum (ER), while AtRMR2 was targeted to the trans-Golgi network (TGN) due to the presence of a cytosolic 23-amino acid sequence linker. The fusion of this linker to an equivalent position in AtRMR1 targeted this receptor to the TGN, instead of the ER. By using a Bimolecular Fluorescent Complementation (BiFC) technique and experiments of co-localization, we demonstrated that AtRMR2 can make homodimers, and can also interact with AtRMR1 forming heterodimers that locate to the TGN. Such interaction studies strongly suggest that the transmembrane domain and the few amino acids surrounding it, including the sequence linker, are essential for dimerization. These results suggest a new model of AtRMR trafficking and dimerization in the plant secretory pathway. Full article

(This article belongs to the Special Issue Unconventional Proteins and Membranes Traffic)

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Review

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955 KiB

Open AccessReview

Unconventional Secretion of Heat Shock Proteins in Cancer

by Tiago Góss Santos, Vilma Regina Martins and Glaucia Noeli Maroso Hajj

Int. J. Mol. Sci. 2017, 18(5), 946; https://doi.org/10.3390/ijms18050946 - 29 Apr 2017

Cited by 53 | Viewed by 8926

Abstract

Heat shock proteins (HSPs) are abundant cellular proteins involved with protein homeostasis. They have both constitutive and inducible isoforms, whose expression levels are further increased by stress conditions, such as temperature elevation, reduced oxygen levels, infection, inflammation and exposure to toxic substances. In these situations, HSPs exert a pivotal role in offering protection, preventing cell death and promoting cell recovery. Although the majority of HSPs functions are exerted in the cytoplasm and organelles, several lines of evidence reveal that HSPs are able to induce cell responses in the extracellular milieu. HSPs do not possess secretion signal peptides, and their secretion was subject to widespread skepticism until the demonstration of the role of unconventional secretion forms such as exosomes. Secretion of HSPs may confer immune system modulation and be a cell-to-cell mediated form of increasing stress resistance. Thus, there is a wide potential for secreted HSPs in resistance of cancer therapy and in the development new therapeutic strategies. Full article

(This article belongs to the Special Issue Unconventional Proteins and Membranes Traffic)

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1781 KiB

Open AccessReview

Annexins as Overlooked Regulators of Membrane Trafficking in Plant Cells

by Dorota Konopka-Postupolska and Greg Clark

Int. J. Mol. Sci. 2017, 18(4), 863; https://doi.org/10.3390/ijms18040863 - 19 Apr 2017

Cited by 47 | Viewed by 9319

Abstract

Annexins are an evolutionary conserved superfamily of proteins able to bind membrane phospholipids in a calcium-dependent manner. Their physiological roles are still being intensively examined and it seems that, despite their general structural similarity, individual proteins are specialized toward specific functions. However, due to their general ability to coordinate membranes in a calcium-sensitive fashion they are thought to participate in membrane flow. In this review, we present a summary of the current understanding of cellular transport in plant cells and consider the possible roles of annexins in different stages of vesicular transport. Full article

(This article belongs to the Special Issue Unconventional Proteins and Membranes Traffic)

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893 KiB

Open AccessReview

Phosphoinositides, Major Actors in Membrane Trafficking and Lipid Signaling Pathways

by Johan-Owen De Craene, Dimitri L. Bertazzi, Séverine Bär and Sylvie Friant

Int. J. Mol. Sci. 2017, 18(3), 634; https://doi.org/10.3390/ijms18030634 - 15 Mar 2017

Cited by 150 | Viewed by 14255

Abstract

Phosphoinositides are lipids involved in the vesicular transport of proteins and lipids between the different compartments of eukaryotic cells. They act by recruiting and/or activating effector proteins and thus are involved in regulating various cellular functions, such as vesicular budding, membrane fusion and cytoskeleton dynamics. Although detected in small concentrations in membranes, their role is essential to cell function, since imbalance in their concentrations is a hallmark of many cancers. Their synthesis involves phosphorylating/dephosphorylating positions D3, D4 and/or D5 of their inositol ring by specific lipid kinases and phosphatases. This process is tightly regulated and specific to the different intracellular membranes. Most enzymes involved in phosphoinositide synthesis are conserved between yeast and human, and their loss of function leads to severe diseases (cancer, myopathy, neuropathy and ciliopathy). Full article

(This article belongs to the Special Issue Unconventional Proteins and Membranes Traffic)

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1712 KiB

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Prelysosomal Compartments in the Unconventional Secretion of Amyloidogenic Seeds

by Helena Borland and Frederik Vilhardt

Int. J. Mol. Sci. 2017, 18(1), 227; https://doi.org/10.3390/ijms18010227 - 23 Jan 2017

Cited by 22 | Viewed by 11092

Abstract

A mechanistic link between neuron-to-neuron transmission of secreted amyloid and propagation of protein malconformation cytopathology and disease has recently been uncovered in animal models. An enormous interest in the unconventional secretion of amyloids from neurons has followed. Amphisomes and late endosomes are the penultimate maturation products of the autophagosomal and endosomal pathways, respectively, and normally fuse with lysosomes for degradation. However, under conditions of perturbed membrane trafficking and/or lysosomal deficiency, prelysosomal compartments may instead fuse with the plasma membrane to release any contained amyloid. After a brief introduction to the endosomal and autophagosomal pathways, we discuss the evidence for autophagosomal secretion (exophagy) of amyloids, with a comparative emphasis on Aβ_1–42 and α-synuclein, as luminal and cytosolic amyloids, respectively. The ESCRT-mediated import of cytosolic amyloid into late endosomal exosomes, a known vehicle of transmission of macromolecules between cells, is also reviewed. Finally, mechanisms of lysosomal dysfunction, deficiency, and exocytosis are exemplified in the context of genetically identified risk factors, mainly for Parkinson’s disease. Exocytosis of prelysosomal or lysosomal organelles is a last resort for clearance of cytotoxic material and alleviates cytopathy. However, they also represent a vehicle for the concentration, posttranslational modification, and secretion of amyloid seeds. Full article

(This article belongs to the Special Issue Unconventional Proteins and Membranes Traffic)

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899 KiB

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Unconventional Pathways of Secretion Contribute to Inflammation

by Michael J. D. Daniels and David Brough

Int. J. Mol. Sci. 2017, 18(1), 102; https://doi.org/10.3390/ijms18010102 - 5 Jan 2017

Cited by 41 | Viewed by 10743

Abstract

In the conventional pathway of protein secretion, leader sequence-containing proteins leave the cell following processing through the endoplasmic reticulum (ER) and Golgi body. However, leaderless proteins also enter the extracellular space through mechanisms collectively known as unconventional secretion. Unconventionally secreted proteins often have vital roles in cell and organism function such as inflammation. Amongst the best-studied inflammatory unconventionally secreted proteins are interleukin (IL)-1β, IL-1α, IL-33 and high-mobility group box 1 (HMGB1). In this review we discuss the current understanding of the unconventional secretion of these proteins and highlight future areas of research such as the role of nuclear localisation. Full article

(This article belongs to the Special Issue Unconventional Proteins and Membranes Traffic)

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1762 KiB

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Subcellular Trafficking of Mammalian Lysosomal Proteins: An Extended View

by Catherine Staudt, Emeline Puissant and Marielle Boonen

Int. J. Mol. Sci. 2017, 18(1), 47; https://doi.org/10.3390/ijms18010047 - 28 Dec 2016

Cited by 66 | Viewed by 16730

Abstract

Lysosomes clear macromolecules, maintain nutrient and cholesterol homeostasis, participate in tissue repair, and in many other cellular functions. To assume these tasks, lysosomes rely on their large arsenal of acid hydrolases, transmembrane proteins and membrane-associated proteins. It is therefore imperative that, post-synthesis, these proteins are specifically recognized as lysosomal components and are correctly sorted to this organelle through the endosomes. Lysosomal transmembrane proteins contain consensus motifs in their cytosolic regions (tyrosine- or dileucine-based) that serve as sorting signals to the endosomes, whereas most lysosomal acid hydrolases acquire mannose 6-phosphate (Man-6-P) moieties that mediate binding to two membrane receptors with endosomal sorting motifs in their cytosolic tails. These tyrosine- and dileucine-based motifs are tickets for boarding in clathrin-coated carriers that transport their cargo from the trans-Golgi network and plasma membrane to the endosomes. However, increasing evidence points to additional mechanisms participating in the biogenesis of lysosomes. In some cell types, for example, there are alternatives to the Man-6-P receptors for the transport of some acid hydrolases. In addition, several “non-consensus” sorting motifs have been identified, and atypical transport routes to endolysosomes have been brought to light. These “unconventional” or “less known” transport mechanisms are the focus of this review. Full article

(This article belongs to the Special Issue Unconventional Proteins and Membranes Traffic)

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2194 KiB

Open AccessConference Report

Unconventional Transport Routes of Soluble and Membrane Proteins and Their Role in Developmental Biology

by Andrea Pompa, Francesca De Marchis, Maria Teresa Pallotta, Yoselin Benitez-Alfonso, Alexandra Jones, Kerstin Schipper, Kevin Moreau, Viktor Žárský, Gian Pietro Di Sansebastiano and Michele Bellucci

Int. J. Mol. Sci. 2017, 18(4), 703; https://doi.org/10.3390/ijms18040703 - 25 Mar 2017

Cited by 29 | Viewed by 8692

Abstract

Many proteins and cargoes in eukaryotic cells are secreted through the conventional secretory pathway that brings proteins and membranes from the endoplasmic reticulum to the plasma membrane, passing through various cell compartments, and then the extracellular space. The recent identification of an increasing number of leaderless secreted proteins bypassing the Golgi apparatus unveiled the existence of alternative protein secretion pathways. Moreover, other unconventional routes for secretion of soluble or transmembrane proteins with initial endoplasmic reticulum localization were identified. Furthermore, other proteins normally functioning in conventional membrane traffic or in the biogenesis of unique plant/fungi organelles or in plasmodesmata transport seem to be involved in unconventional secretory pathways. These alternative pathways are functionally related to biotic stress and development, and are becoming more and more important in cell biology studies in yeast, mammalian cells and in plants. The city of Lecce hosted specialists working on mammals, plants and microorganisms for the inaugural meeting on “Unconventional Protein and Membrane Traffic” (UPMT) during 4–7 October 2016. The main aim of the meeting was to include the highest number of topics, summarized in this report, related to the unconventional transport routes of protein and membranes. Full article

(This article belongs to the Special Issue Unconventional Proteins and Membranes Traffic)

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