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Breaking New Cell Biology Research

How can a cytosolic autophagy machinery "eat" parts of the nucleus? New work from LusKing and Melia labs provide an answer.

It is known that pathological protein aggregates can accumulate within the nucleus and can be cleared by a cytosolic autophagy machinery. However, the underlying mechanisms that allow the autophagosome to "see" aberrant proteins that are hidden by the double membrane of the nuclear envelope remains unknown. In a collaborative work, Sunandini Chandra, Philip Mannino and David Thaller provide compelling new evidence for an outside-in mechanism where a transmembrane cargo adaptor localizes at the outer nuclear membrane and reaches across the nuclear envelope lumen to capture the inner nuclear membrane into vesicles that can be ultimately captured by the autophagosome.

Source: Journal of Cell Biology
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  • Imaging tissue samples at sub-50 nm resolution in 3D by light microscopy

    Light microscopy is traditionally limited by diffraction to about 250 nm resolution in the focal plane and more than 500 nm in depth. Super-resolution STED microscopy has overcome this diffraction limit but achieving sub-100 nm super-resolution in 3D in the middle of a tissue section has been impossible due to the optical aberrations the tissue introduces into the optical beam path. Introducing adaptive optics into an isoSTED microscope, an instrument that utilizes two opposing objectives for optimal 3D resolution, allowed the authors to correct for these aberrations. Using this instrument, they were able to obtain for the first time multi-color sub-50 nm 3D resolution images in samples as complex as Drosophila egg chambers and mouse brain tissue sections.

    Source: Nature Methods
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  • Phospholipase PLCγ1 promotes phase separation in T cells

    Phospholipase Cγ1 (PLCγ1) hydrolyzes PIP2 to generate IP3 and DAG to transduce T cell receptor (TCR) signaling. We revealed a lipase-independent function of PLCγ1 in promoting phase separation of T cell signaling components. We showed that PLCγ1crosslinks LAT, a key adaptor protein in forming signaling condensates in the TCR pathway. PLCγ1 also protects LAT from CD45-mediated dephosphorylation and promotes downstream ERK activation and actin polymerization. Interestingly, PLCγ1 promotes LAT condensation only at low concentrations but not high concentrations. This could be explained by a change in internal organization of the condensates using a coarse-grained model-based simulation.

    Source: Journal of Cell Biology
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  • DNA helps sort out liposomes and biophysical problems

    Small liposomes of uniform sizes are valuable tools for studying membrane biology and developing drug-delivery vehicles. Now, using a DNA-assisted sorting technique, multiple species of monodispersed liposomes with mean diameters below 150 nm can be produced in a scalable manner, enabling high-resolution analyses of curvature-dependent membrane protein activates.

    Source: Nature Chemistry
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  • Mechanotransduction regulates epidermal differentiation

    This collaboration between the Horsley lab (MCDB) and Lusk/King lab (Cell Biology and MCDB) led to the discovery that a molecular bridge spanning the nuclear envelope (the LINC complex) is under mechanical load in response to the extracellular environment as engaged and sensed by a class of cell surface receptors called integrins. This force transduction mechanism plays an important role in regulating epidermal differentiation in mice, suggesting that LINC complexes propagate mechanical signals to the nucleus, where they impact on the accessibility and expression of genes important for epidermal differentiation.

    Source: eLife
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  • Proteins get together in the ER for a shared journey to lysosomes

    New research from the Ferguson lab investigates how progranulin and prosaposin, two lysosome proteins linked to neurodegenerative diseases are trafficked to lysosomes. Their observations support a model wherein newly translated progranulin and prosaposin interact within the lumen of the ER and bind via prosaposin to Surf4 for their packaging into COPII vesicles for delivery to the Golgi. These new findings concerning progranulin and prosaposin engaging in Surf4-dependent trafficking early in the secretory pathway complement the previous studies that defined later roles for the CI-MPR, LRP1 and sortilin at the trans-Golgi network and the plasma membrane. Each of these regulated trafficking events will contribute to how efficiently the progranulin-prosaposin complex is delivered to lysosomes and is thus of fundamental cell biological relevance and of potential value for future strategies to enhance progranulin trafficking for therapeutic purposes in neurodegenerative diseases.

    Source: bioRxiv
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  • A new mechanism by which insulin regulates the production of body heat

    Insulin stimulates the ubiquitin-like proteolytic processing of TUG proteins to mobilize GLUT4 glucose transporters present in vesicles that are trapped at the Golgi matrix. These vesicles then fuse at the cell surface, inserting GLUT4 into the plasma membrane to increase glucose uptake. This work shows that that after TUG cleavage, the C-terminal cleavage product enters the nucleus and regulates the transcription of genes to cause fatty acid oxidation and production of body heat. The extent and duration of this thermogenic effect is controlled by an Arg/N-degron pathway that regulates the stability of the TUG product.

    Source: Nature Metabolism
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  • Conditional targeting of phosphatidylserine decarboxylase to lipid droplets

    Phosphatidylethanolamine (PE) is an abundant component of cellular membranes. An evolutionarily ancient mechanism for producing PE is to decarboxylate phosphatidylserine and the enzyme catalyzing this reaction, phosphatidylserine decarboxylase, localizes to the inner membrane of the mitochondrion. We discovered that a second form of phosphatidylserine decarboxylase, termed PISD-LD, is generated by alternative splicing of PISD pre-mRNA. Targeting of PISD-LD in the cell is regulated by nutritional state; growth conditions that promote neutral lipid storage in lipid droplets favors targeting of PISD-LD to lipid droplets, while targeting to mitochondria is favored by conditions that promote consumption of lipid droplets. Depletion of both forms of phosphatidylserine decarboxylase impairs triacylglycerol synthesis when cells are challenged with free fatty acid, indicating a crucial role phosphatidylserine decarboxylase in neutral lipid storage.

    Source: Biology Open
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