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Clinical Case Reports Apr 2024Plasma cell myeloma is a rare entity in the pediatric population. The peak incidence is in the seventh decade, with less than 2% of cases occurring in patients under the...
KEY CLINICAL MESSAGE
Plasma cell myeloma is a rare entity in the pediatric population. The peak incidence is in the seventh decade, with less than 2% of cases occurring in patients under the age of 40. It is worth noting that any destructive bony lesion in a child should be investigated.
ABSTRACT
Plasma cell myeloma (multiple myeloma) is the most common form of plasma cell neoplasm. It is a rare entity in young patients. The peak incidence is in the seventh decade, with less than 2% of cases occurring in patients under the age of 40. A male patient aged 9 years old with a progressive pain in lower back for about 1 month, aggravated by bending, associated with inability to stand upright, no any history of trauma. He complained about left pin-point chest pain, no any history of febrile illness. MRI showed a mass lesion of the L3 vertebra; CT scan revealed osteolytic lesions in the left T12, S2-sacral region, and left calvarium. Histology report of L3 lesion revealed cells with an eccentric nucleus, prominent Golgi apparatus and Flow cytometry revealed cells stained positive for CD 138 and CD56 and negative for CD45 expression. In situ hybridization identified k-light chain band restriction. Bone marrow evaluation was normal. A small serum monoclonal immunoglobin A spike of k-light chain type was noted. Other tests like complete blood count, lactate dehydrogenase levels, renal functional tests, and B2-microglobulin were normal. A diagnosis of plasma cell myeloma was made and the patient was started on emergent radiation to L3 lesion due to progressive neurological symptoms followed systemic therapy which resulted int reduction of L3 lesion. Plasma cell myeloma is extremely rare form of liquid tumor in the pediatric population, and it is important for any destructive bony lesion in a child to have appropriate work up.
PubMed: 38645602
DOI: 10.1002/ccr3.8801 -
ELife Apr 2024Mapping proteins in and associated with the Golgi apparatus reveals how this cellular compartment emerges in budding yeast and progresses over time.
Mapping proteins in and associated with the Golgi apparatus reveals how this cellular compartment emerges in budding yeast and progresses over time.
Topics: Golgi Apparatus; Saccharomycetales
PubMed: 38629949
DOI: 10.7554/eLife.97430 -
Cellular & Molecular Biology Letters Apr 2024The trafficking of cargoes from endosomes to the trans-Golgi network requires numerous sequential and coordinated steps. Cargoes are sorted into endosomal-derived...
BACKGROUND
The trafficking of cargoes from endosomes to the trans-Golgi network requires numerous sequential and coordinated steps. Cargoes are sorted into endosomal-derived carriers that are transported, tethered, and fused to the trans-Golgi network. The tethering step requires several complexes, including the Golgi-associated retrograde protein complex, whose localization at the trans-Golgi network is determined by the activity of small GTPases of the Arl and Rab family. However, how the Golgi-associated retrograde protein complex recognizes the endosome-derived carriers that will fuse with the trans-Golgi network is still unknown.
METHODS
We studied the retrograde trafficking to the trans-Golgi network by using fluorescent cargoes in cells overexpressing Rab4b or after Rab4b knocked-down by small interfering RNA in combination with the downregulation of subunits of the Golgi-associated retrograde protein complex. We used immunofluorescence and image processing (Super Resolution Radial Fluctuation and 3D reconstruction) as well as biochemical approaches to characterize the consequences of these interventions on cargo carriers trafficking.
RESULTS
We reported that the VPS52 subunit of the Golgi-associated retrograde protein complex is an effector of Rab4b. We found that overexpression of wild type or active Rab4b increased early endosomal to trans-Golgi network retrograde trafficking of the cation-independent mannose-6-phosphate receptor in a Golgi-associated retrograde protein complex-dependent manner. Conversely, overexpression of an inactive Rab4b or Rab4b knockdown attenuated this trafficking. In the absence of Rab4b, the internalized cation-independent mannose 6 phosphate receptor did not have access to VPS52-labeled structures that look like endosomal subdomains and/or endosome-derived carriers, and whose subcellular distribution is Rab4b-independent. Consequently, the cation-independent mannose-6-phosphate receptor was blocked in early endosomes and no longer had access to the trans-Golgi network.
CONCLUSION
Our results support that Rab4b, by controlling the sorting of the cation-independent mannose-6-phosphate receptor towards VPS52 microdomains, confers a directional specificity for cargo carriers en route to the trans-Golgi network. Given the importance of the endocytic recycling in cell homeostasis, disruption of the Rab4b/Golgi-associated retrograde protein complex-dependent step could have serious consequences in pathologies.
Topics: Cations; Endosomes; Golgi Apparatus; Protein Transport; Receptor, IGF Type 2; trans-Golgi Network
PubMed: 38627612
DOI: 10.1186/s11658-024-00574-w -
PLoS Pathogens Apr 2024Kaposi's sarcoma-associated herpesvirus (KSHV) is a double-stranded DNA virus etiologically associated with multiple malignancies. Both latency and sporadic lytic...
Kaposi's sarcoma-associated herpesvirus (KSHV) is a double-stranded DNA virus etiologically associated with multiple malignancies. Both latency and sporadic lytic reactivation contribute to KSHV-associated malignancies, however, the specific roles of many KSHV lytic gene products in KSHV replication remain elusive. In this study, we report that ablation of ORF55, a late gene encoding a tegument protein, does not impact KSHV lytic reactivation but significantly reduces the production of progeny virions. We found that cysteine 10 and 11 (C10 and C11) of pORF55 are palmitoylated, and the palmytoilation is essential for its Golgi localization and secondary envelope formation. Palmitoylation-defective pORF55 mutants are unstable and undergo proteasomal degradation. Notably, introduction of a putative Golgi localization sequence to these palmitoylation-defective pORF55 mutants restores Golgi localization and fully reinstates KSHV progeny virion production. Together, our study provides new insight into the critical role of pORF55 palmitoylation in KSHV progeny virion production and offers potential therapeutic targets for the treatment of related malignancies.
Topics: Herpesvirus 8, Human; Golgi Apparatus; Humans; Lipoylation; Virion; Viral Proteins; Virus Replication; HEK293 Cells
PubMed: 38626263
DOI: 10.1371/journal.ppat.1012141 -
PLoS Pathogens Apr 2024African swine fever (ASF) is an acute, hemorrhagic, and severe infectious disease caused by the ASF virus (ASFV). ASFV has evolved multiple strategies to escape host...
African swine fever (ASF) is an acute, hemorrhagic, and severe infectious disease caused by the ASF virus (ASFV). ASFV has evolved multiple strategies to escape host antiviral immune responses. Here, we reported that ASFV pB318L, a trans-geranylgeranyl-diphosphate synthase, reduced the expression of type I interferon (IFN-I) and IFN-stimulated genes (ISGs). Mechanically, pB318L not only interacted with STING to reduce the translocation of STING from the endoplasmic reticulum to the Golgi apparatus but also interacted with IFN receptors to reduce the interaction of IFNAR1/TYK2 and IFNAR2/JAK1. Of note, ASFV with interruption of B318L gene (ASFV-intB318L) infected PAMs produces more IFN-I and ISGs than that in PAMs infected with its parental ASFV HLJ/18 at the late stage of infection. Consistently, the pathogenicity of ASFV-intB318L is attenuated in piglets compared with its parental virus. Taken together, our data reveal that B318L gene may partially affect ASFV pathogenicity by reducing the production of IFN-I and ISGs. This study provides a clue to design antiviral agents or live attenuated vaccines to prevent and control ASF.
Topics: Animals; Swine; African Swine Fever Virus; African Swine Fever; Farnesyltranstransferase; Viral Proteins; Nucleotidyltransferases; Interferon Type I; Signal Transduction
PubMed: 38620034
DOI: 10.1371/journal.ppat.1012136 -
International Journal of Molecular... Apr 2024The Golgi apparatus, long recognized for its roles in protein processing and vesicular trafficking, has recently been identified as a crucial contributor to innate... (Review)
Review
The Golgi apparatus, long recognized for its roles in protein processing and vesicular trafficking, has recently been identified as a crucial contributor to innate immune signaling pathways. This review discusses our expanding understanding of the Golgi apparatus's involvement in initiating and activating these pathways. It highlights the significance of membrane connections between the Golgi and other organelles, such as the endoplasmic reticulum, mitochondria, endosomes, and autophagosomes. These connections are vital for the efficient transmission of innate immune signals and the activation of effector responses. Furthermore, the article delves into the Golgi apparatus's roles in key immune pathways, including the inflammasome-mediated activation of caspase-1, the -STING pathway, and TLR/RLR signaling. Overall, this review aims to provide insights into the multifunctional nature of the Golgi apparatus and its impact on innate immunity.
Topics: Golgi Apparatus; Immunity, Innate; Inflammasomes; Autophagosomes; Caspase 1
PubMed: 38612929
DOI: 10.3390/ijms25074120 -
Cell Stress & Chaperones Jun 2024Anhydrobiotic species can survive virtually complete water loss by entering a reversible ametabolic glassy state that may persist for years in ambient conditions. The...
Anhydrobiotic species can survive virtually complete water loss by entering a reversible ametabolic glassy state that may persist for years in ambient conditions. The Pv11 cell line was derived from the egg mass of the anhydrobiotic midge, Polypedilum vanderplanki, and is currently the only available anhydrobiotic cell line. Our results demonstrate that the necessary preconditioning for Pv11 cells to enter anhydrobiosis causes autophagy and reduces mitochondrial respiration by over 70%. We speculate that reorganizing cellular bioenergetics to create and conserve energy stores may be valuable to successfully recover after rehydration. Furthermore, mitochondria in preconditioned cells lose their membrane potential during desiccation but rapidly restore it within 30 min upon rehydration, demonstrating that the inner mitochondrial membrane integrity is well-preserved. Strikingly, the nucleolus remains visible immediately upon rehydration in preconditioned cells while absent in control cells. In contrast, a preconditioning-induced membraneless organelle reformed after rehydration, demonstrating that membraneless organelles in Pv11 cells can be either stabilized or recovered. Staining the endoplasmic reticulum and the Golgi apparatus revealed that these organelles fragment during preconditioning. We hypothesize that this process reduces sheering stress caused by rapid changes in cellular volume during desiccation and rehydration. Additionally, preconditioning was found to cause the filamentous-actin (F-actin) network to disassemble significantly and reduce the fusion of adjacent plasma membranes. This study offers several exciting avenues for future studies in the animal model and Pv11 cell line that will further our understanding of anhydrobiosis and may lead to advancements in storing sensitive biologics at ambient temperatures for months or years.
Topics: Animals; Cell Line; Desiccation; Mitochondria; Organelles; Autophagy; Endoplasmic Reticulum; Golgi Apparatus
PubMed: 38608858
DOI: 10.1016/j.cstres.2024.04.002 -
Nature Communications Apr 2024Autophagy is a conserved, catabolic process essential for maintaining cellular homeostasis. Malfunctional autophagy contributes to neurodevelopmental and...
Autophagy is a conserved, catabolic process essential for maintaining cellular homeostasis. Malfunctional autophagy contributes to neurodevelopmental and neurodegenerative diseases. However, the exact role and targets of autophagy in human neurons remain elusive. Here we report a systematic investigation of neuronal autophagy targets through integrated proteomics. Deep proteomic profiling of multiple autophagy-deficient lines of human induced neurons, mouse brains, and brain LC3-interactome reveals roles of neuronal autophagy in targeting proteins of multiple cellular organelles/pathways, including endoplasmic reticulum (ER), mitochondria, endosome, Golgi apparatus, synaptic vesicle (SV) for degradation. By combining phosphoproteomics and functional analysis in human and mouse neurons, we uncovered a function of neuronal autophagy in controlling cAMP-PKA and c-FOS-mediated neuronal activity through selective degradation of the protein kinase A - cAMP-binding regulatory (R)-subunit I (PKA-RI) complex. Lack of AKAP11 causes accumulation of the PKA-RI complex in the soma and neurites, demonstrating a constant clearance of PKA-RI complex through AKAP11-mediated degradation in neurons. Our study thus reveals the landscape of autophagy degradation in human neurons and identifies a physiological function of autophagy in controlling homeostasis of PKA-RI complex and specific PKA activity in neurons.
Topics: Mice; Animals; Humans; Proteomics; Neurons; Cyclic AMP-Dependent Protein Kinases; Autophagy; Homeostasis
PubMed: 38600097
DOI: 10.1038/s41467-024-47440-z -
Molecular & Cellular Proteomics : MCP May 2024Glycoproteins located on the cell surface play a pivotal role in nearly every extracellular activity. N-glycosylation is one of the most common and important protein...
Glycoproteins located on the cell surface play a pivotal role in nearly every extracellular activity. N-glycosylation is one of the most common and important protein modifications in eukaryotic cells, and it often regulates protein folding and trafficking. Glycosylation of cell-surface proteins undergoes meticulous regulation by various enzymes in the endoplasmic reticulum (ER) and the Golgi, ensuring their proper folding and trafficking to the cell surface. However, the impacts of protein N-glycosylation, N-glycan maturity, and protein folding status on the trafficking of cell-surface glycoproteins remain to be explored. In this work, we comprehensively and site-specifically studied the trafficking of cell-surface glycoproteins in human cells. Integrating metabolic labeling, bioorthogonal chemistry, and multiplexed proteomics, we investigated 706 N-glycosylation sites on 396 cell-surface glycoproteins in monocytes, either by inhibiting protein N-glycosylation, disturbing N-glycan maturation, or perturbing protein folding in the ER. The current results reveal their distinct impacts on the trafficking of surface glycoproteins. The inhibition of protein N-glycosylation dramatically suppresses the trafficking of many cell-surface glycoproteins. The N-glycan immaturity has more substantial effects on proteins with high N-glycosylation site densities, while the perturbation of protein folding in the ER exerts a more pronounced impact on surface glycoproteins with larger sizes. Furthermore, for N-glycosylated proteins, their trafficking to the cell surface is related to the secondary structures and adjacent amino acid residues of glycosylation sites. Systematic analysis of surface glycoprotein trafficking advances our understanding of the mechanisms underlying protein secretion and surface presentation.
Topics: Humans; Glycosylation; Protein Transport; Endoplasmic Reticulum; Polysaccharides; Glycoproteins; Cell Membrane; Protein Folding; Proteomics; Membrane Glycoproteins; Golgi Apparatus; Protein Processing, Post-Translational
PubMed: 38593903
DOI: 10.1016/j.mcpro.2024.100761 -
Cellular and Molecular Life Sciences :... Apr 2024Kinesin family member 3A (KIF3A) is a microtubule-oriented motor protein that belongs to the kinesin-2 family for regulating intracellular transport and microtubule...
Kinesin family member 3A (KIF3A) is a microtubule-oriented motor protein that belongs to the kinesin-2 family for regulating intracellular transport and microtubule movement. In this study, we characterized the critical roles of KIF3A during mouse oocyte meiosis. We found that KIF3A associated with microtubules during meiosis and depletion of KIF3A resulted in oocyte maturation defects. LC-MS data indicated that KIF3A associated with cell cycle regulation, cytoskeleton, mitochondrial function and intracellular transport-related molecules. Depletion of KIF3A activated the spindle assembly checkpoint, leading to metaphase I arrest of the first meiosis. In addition, KIF3A depletion caused aberrant spindle pole organization based on its association with KIFC1 to regulate expression and polar localization of NuMA and γ-tubulin; and KIF3A knockdown also reduced microtubule stability due to the altered microtubule deacetylation by histone deacetylase 6 (HDAC6). Exogenous Kif3a mRNA supplementation rescued the maturation defects caused by KIF3A depletion. Moreover, KIF3A was also essential for the distribution and function of mitochondria, Golgi apparatus and endoplasmic reticulum in oocytes. Conditional knockout of epithelial splicing regulatory protein 1 (ESRP1) disrupted the expression and localization of KIF3A in oocytes. Overall, our results suggest that KIF3A regulates cell cycle progression, spindle assembly and organelle distribution during mouse oocyte meiosis.
Topics: Animals; Mice; Biological Transport; Kinesins; Meiosis; Metaphase; Oocytes
PubMed: 38587639
DOI: 10.1007/s00018-024-05213-3