Breaking New Cell Biology Research

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.

Jacob A. Culver and Malaiyalam Mariappan show that newly synthesized tail-anchored proteins are polyubiquitinated and yet are targeted properly, deubiquitinated, and inserted into the ER membrane.

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.

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.

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.

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.

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.

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.

Pioneering new work from the Colon-Ramos lab visualizes brain development in real time in a worm embryo.