Breaking New Cell Biology Research

The brain has its own housekeeping service, a sophisticated mechanism that cleans up debris that is left over from cellular activity. But scientists have had a hard time figuring out exactly how the brain knows when to initiate this cellular “trash pickup.”

New research from the De Camilli and Ferguson labs reveals a close relationship between the transport of lysosomes and cytoskeleton organization in neuronal axons through studies of human ipSC-derived neurons lacking JIP3/MAPK8IP3, a scaffold protein that is thought to link lysosomes to motors. These findings raise new questions about how the transport of cargos is coordinated with the structure and dynamics of multiple components of the axonal cytoskeleton. Answers to these questions may be relevant to human neurdevelopmental disease arising from mutations in the JIP3/MAPK8IP3 gene as well as for Alzheimer’s disease where lysosomes accumulate in axonal swellings at amyloid plaques.

Progranulin and prosaposin are critical regulators of lysosome hydrolase activity and mutations in the progranulin and prosaposin genes cause neurological diseases. Most notably, frontotemporal dementia arising from progranulin haploinsufficiency. The importance of these proteins within lysosomes has stimulated interested in factors that regulate their trafficking to lysosomes. In this new study, Swathi Devireddy and Shawn Ferguson discover that newly made progranulin and prosaposin get together in the endoplasmic reticulum and the trafficking of progranulin out of the endoplasmic reticulum is promoted by this interaction. Efficient endoplasmic reticulum exit of the progranulin-prosaposin complex is mediated by an interaction between prosaposin and Surf4, a receptor for COPII vesicles. This pathway for prioritizing the trafficking of progranulin and prosaposin out of the endoplasmic reticulum is critical for ensuring efficient delivery of progranulin and prosaposin to lysosomes.

The Burd and von Blume labs have published a poster summarizes protein sorting mechanisms operating in the Golgi apparatus during secretion. The poster is intended to serve as a primer for colleagues who are not familiar with this area of cell biology.

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.

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.

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.