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International Journal of Molecular... Aug 2023Gene expression in eukaryotes begins with transcription in the nucleus, followed by the synthesis of messenger RNA (mRNA), which is then exported to the cytoplasm for... (Review)
Review
Gene expression in eukaryotes begins with transcription in the nucleus, followed by the synthesis of messenger RNA (mRNA), which is then exported to the cytoplasm for its translation into proteins. Along with transcription and translation, mRNA export through the nuclear pore complex (NPC) is an essential regulatory step in eukaryotic gene expression. Multiple factors regulate mRNA export and hence gene expression. Interestingly, proteins from certain types of viruses interact with these factors in infected cells, and such an interaction interferes with the mRNA export of the host cell in favor of viral RNA export. Thus, these viruses hijack the host mRNA nuclear export mechanism, leading to a reduction in host gene expression and the downregulation of immune/antiviral responses. On the other hand, the viral mRNAs successfully evade the host surveillance system and are efficiently exported from the nucleus to the cytoplasm for translation, which enables the continuation of the virus life cycle. Here, we present this review to summarize the mechanisms by which viruses suppress host mRNA nuclear export during infection, as well as the key strategies that viruses use to facilitate their mRNA nuclear export. These studies have revealed new potential antivirals that may be used to inhibit viral mRNA transport and enhance host mRNA nuclear export, thereby promoting host gene expression and immune responses.
Topics: Humans; Active Transport, Cell Nucleus; Virus Diseases; Antiviral Agents; RNA Transport; Eukaryota; RNA, Messenger
PubMed: 37628773
DOI: 10.3390/ijms241612593 -
International Journal of Biological... 2024The mechanism that maintains ER-to-Golgi vesicles formation and transport is complicated. As one of the adapters, Ninein-like protein (Nlp) participated in assembly and...
The mechanism that maintains ER-to-Golgi vesicles formation and transport is complicated. As one of the adapters, Ninein-like protein (Nlp) participated in assembly and transporting of partial ER-to-Golgi vesicles that contained specific proteins, such as β-Catenin and STING. Nlp acted as a platform to sustain the specificity and continuity of cargoes during COPII and COPI-coated vesicle transition and transportation through binding directly with SEC31A as well as Rab1B. Thus, we proposed an integrated transport model that particular adapter participated in specific cargo selection or transportation through cooperating with different membrane associated proteins to ensure the continuity of cargo trafficking. Deficiency of Nlp led to vesicle budding failure and accumulation of unprocessed proteins in ER, which further caused ER stress as well as Golgi fragmentation, and PERK-eIF2α pathway of UPR was activated to reduce the synthesis of universal proteins. In contrast, upregulation of Nlp resulted in Golgi fragmentation, which enhanced the cargo transport efficiency between ER and Golgi. Moreover, deficient mice were prone to spontaneous B cell lymphoma, since the developments and functions of lymphocytes significantly depended on secretory proteins through ER-to-Golgi vesicle trafficking, including IL-13, IL-17 and IL-21. Thus, perturbations of Nlp altered ER-to-Golgi communication and cellular homeostasis, and might contribute to the pathogenesis of B cell lymphoma.
Topics: Animals; Humans; Mice; COP-Coated Vesicles; Endoplasmic Reticulum; Golgi Apparatus; Protein Transport
PubMed: 38904019
DOI: 10.7150/ijbs.91792 -
Methods in Molecular Biology (Clifton,... 2024Many computational methods are available for predicting protein sorting in bacteria. When comparing them, it is important to know that they can be grouped into three...
Many computational methods are available for predicting protein sorting in bacteria. When comparing them, it is important to know that they can be grouped into three fundamentally different approaches: signal-based, global property-based, and homology-based prediction. In this chapter, the strengths and drawbacks of each of these approaches are described through many examples of methods that predict secretion, integration into membranes, or subcellular locations in general. The aim of this chapter is to provide a user-level introduction to the field with a minimum of computational theory.
Topics: Protein Transport
PubMed: 37930519
DOI: 10.1007/978-1-0716-3445-5_2 -
International Journal of Medical... 2023The members of the transmembrane emp24 domain-containing protein (TMED) family are summarized in human as four subfamilies, α (TMED 4, 9), β (TMED 2), γ (TMED1, 3, 5,... (Review)
Review
The members of the transmembrane emp24 domain-containing protein (TMED) family are summarized in human as four subfamilies, α (TMED 4, 9), β (TMED 2), γ (TMED1, 3, 5, 6, 7) and δ (TMED 10), with a total of nine members, which are important regulators of intracellular protein transport and are involved in normal embryonic development, as well as in the pathogenic processes of many human diseases. Here we systematically review the composition, structure and function of TMED family members, and describe the progress of TMED family in human diseases, including malignancies (head and neck tumors, lung cancer, breast cancer, ovarian cancer, endometrial cancer, gastrointestinal tumors, urological tumors, osteosarcomas, etc.), immune responses, diabetes, neurodegenerative diseases, and nonalcoholic fatty liver disease, dilated cardiomyopathy, mucin 1 nephropathy (MKD), and desiccation syndrome (SS). Finally, we discuss and prospect the potential of TMED for disease prognosis prediction and therapeutic targeting, with a view to laying the foundation for therapeutic research based on TMED family causative genes.
Topics: Pregnancy; Female; Humans; Membrane Proteins; Protein Transport; Non-alcoholic Fatty Liver Disease; Vesicular Transport Proteins
PubMed: 37928880
DOI: 10.7150/ijms.87272 -
Advanced Science (Weinheim,... Oct 2023Tissue-infiltrating neutrophils (TINs) secrete various signaling molecules to establish paracrine communication within the inflammatory milieu. It is imperative to...
Tissue-infiltrating neutrophils (TINs) secrete various signaling molecules to establish paracrine communication within the inflammatory milieu. It is imperative to identify molecular mediators that control this secretory phenotype of TINs. The present study uncovers a secretory neutrophil subset that exhibits increased pro-inflammatory cytokine production and enhanced migratory capacity which is highly related with periodontal pathogenesis. Further analysis identifies the OTU domain-containing protein 1 (OTUD1) plays a regulatory role in this secretory neutrophil polarization. In human and mouse periodontitis, the waning of inflammation is correlated with OTUD1 upregulation, whereas severe periodontitis is induced when neutrophil-intrinsic OTUD1 is depleted. Mechanistically, OTUD1 interacts with SEC23B, a component of the coat protein II complex (COPII). By removing the K63-linked polyubiquitin chains on SEC23B Lysine 81, the deubiquitinase OTUD1 negatively regulates the COPII secretory machinery and limits protein ER-to-Golgi trafficking, thus restricting the surface expression of integrin-regulated proteins, CD9 and CD47. Accordingly, blockade of protein transport by Brefeldin A (BFA) curbs recruitment of Otud1-deficient TINs and attenuates inflammation-induced alveolar bone destruction. The results thus identify OTUD1 signaling as a negative feedback loop that limits the polarization of neutrophils with secretory phenotype and highlight the potential application of BFA in the treatment of periodontal inflammation.
Topics: Animals; Humans; Mice; Deubiquitinating Enzymes; Inflammation; Neutrophils; Periodontitis; Protein Transport; Ubiquitin-Specific Proteases
PubMed: 37639212
DOI: 10.1002/advs.202303207 -
Antiviral Research Jan 2024The endosomal sorting complex required for transport (ESCRT) machinery plays a significant role in the spread of human viruses. However, our understanding of how the... (Review)
Review
The endosomal sorting complex required for transport (ESCRT) machinery plays a significant role in the spread of human viruses. However, our understanding of how the host ESCRT machinery responds to viral infection remains limited. Emerging evidence suggests that the ESCRT machinery can be hijacked by viruses of different families to enhance their replication. Throughout their life cycle, these viruses can interfere with or exploit ESCRT-mediated physiological processes to increase their chances of infecting the host. In contrast, to counteract virus infection, the interferon-stimulated gene 15 (ISG15) or the E3 ISG15-protein ligase (HERC5) system within the infected cells is activated to degrade the ESCRT proteins. Many retroviral and RNA viral proteins have evolved "late (L) domain" motifs, which enable them to recruit host ESCRT subunit proteins to facilitate virus transport, replication, budding, mature, and even endocytosis, Therefore, the L domain motifs and ESCRT subunit proteins could serve as promising drug targets for antiviral therapy. This review investigated the composition and essential functions of the ESCRT, shedding light on the impact of ESCRT subunits and viral L domain motifs on the replication of viruses. Furthermore, the antiviral effects facilitated by the ESCRT machinery have been investigated, aiming to provide valuable insights to guide the development and utilization of antiviral drugs.
Topics: Humans; Endosomal Sorting Complexes Required for Transport; Protein Transport; Viral Proteins; Interferons; Ubiquitin-Protein Ligases; Virus Diseases; Virus Replication; Virus Release
PubMed: 38147902
DOI: 10.1016/j.antiviral.2023.105786 -
Journal of Proteome Research Nov 2023Most proteins secreted into the extracellular space are first recruited from the endoplasmic reticulum into coat protein complex II (COPII)-coated vesicles or tubules...
Most proteins secreted into the extracellular space are first recruited from the endoplasmic reticulum into coat protein complex II (COPII)-coated vesicles or tubules that facilitate their transport to the Golgi apparatus. Although several secreted proteins have been shown to be actively recruited into COPII vesicles and tubules by the cargo receptors LMAN1 and SURF4, the full cargo repertoire of these receptors is unknown. We now report mass spectrometry analysis of conditioned media and cell lysates from HuH7 cells CRISPR targeted to inactivate the or gene. We found that LMAN1 has limited clients in HuH7 cells, whereas SURF4 traffics a broad range of cargoes. Analysis of putative SURF4 cargoes suggests that cargo recognition is governed by complex mechanisms rather than interaction with a universal binding motif..
Topics: Humans; Carrier Proteins; Endoplasmic Reticulum; Golgi Apparatus; Membrane Proteins; Protein Transport
PubMed: 37844105
DOI: 10.1021/acs.jproteome.3c00259 -
Biological Chemistry Jul 2023Most mitochondrial proteins are nuclear-encoded and imported by the protein import machinery based on specific targeting signals. The proteins that carry an...
Most mitochondrial proteins are nuclear-encoded and imported by the protein import machinery based on specific targeting signals. The proteins that carry an amino-terminal targeting signal (presequence) are imported via the presequence import pathway that involves the translocases of the outer and inner membranes - TOM and TIM23 complexes. In this article, we discuss how mitochondrial matrix and inner membrane precursor proteins are imported along the presequence pathway in with a focus on the dynamics of the TIM23 complex, and further update with some of the key findings that advanced the field in the last few years.
Topics: Protein Transport; Saccharomyces cerevisiae; Mitochondria; Mitochondrial Proteins; Mitochondrial Precursor Protein Import Complex Proteins
PubMed: 37155927
DOI: 10.1515/hsz-2023-0133 -
Applied Microbiology and Biotechnology Dec 2024Hyaluronidases catalyze the degradation of hyaluronan (HA), which is finding rising applications in medicine, cosmetic, and food industries. Recombinant expression of...
Hyaluronidases catalyze the degradation of hyaluronan (HA), which is finding rising applications in medicine, cosmetic, and food industries. Recombinant expression of hyaluronidases in microbial hosts has been given special attention as a sustainable way to substitute animal tissue-derived hyaluronidases. In this study, we focused on optimizing the secretion of hyaluronidase from Homo sapiens in Pichia pastoris by secretion pathway engineering. The recombinant hyaluronidase was first expressed under the control of a constitutive promoter P. Then, two endoplasmic reticulum-related secretory pathways were engineered to improve the secretion capability of the recombinant strain. Signal peptide optimization suggested redirecting the protein into co-translational translocation using the ost1-proα signal sequence improved the secretion level by 20%. Enhancing the co-translational translocation by overexpressing signal recognition particle components further enhanced the secretory capability by 48%. Then, activating the unfolded protein response by overexpressing a transcriptional factor ScHac1p led to a secreted hyaluronidase activity of 4.06 U/mL, which was 2.1-fold higher than the original strain. Finally, fed-batch fermentation elevated the production to 19.82 U/mL. The combined engineering strategy described here could be applied to enhance the secretion capability of other proteins in yeast hosts. KEY POINTS: • Improving protein secretion by enhancing co-translational translocation in P. pastoris was reported for the first time. • Overexpressing Hac1p homologous from different origins improved the rhPH-20 secretion. • A 4.9-fold increase in rhPH-20 secretion was achieved after fermentation optimization and fed-batch fermentation.
Topics: Animals; Humans; Hyaluronoglucosaminidase; Protein Transport; Unfolded Protein Response; Endoplasmic Reticulum
PubMed: 38175240
DOI: 10.1007/s00253-023-12878-6 -
ELife May 2024Advanced cryo-EM approaches reveal surprising insights into the molecular structure that allows nascent proteins to be inserted into the membrane of the endoplasmic...
Advanced cryo-EM approaches reveal surprising insights into the molecular structure that allows nascent proteins to be inserted into the membrane of the endoplasmic reticulum.
Topics: Endoplasmic Reticulum; Cryoelectron Microscopy; Protein Transport; Membrane Proteins
PubMed: 38787756
DOI: 10.7554/eLife.98548