Breaking New Cell Biology Research

The manuscript reports the different sorting of ATG9 vesicles and synaptic vesicles in nerve terminals and in an exogenous system

DNA-PAINT is one of the best techniques to image cellular components at 20 nm resolution. New fluorogenic probes eliminate the background light problem this technology suffered from and speed up image acquisition 26-fold. This advance provides unprecedented super-resolution imaging capabilities for applications in Cell Biology.

Molecular chaperones in cells constantly monitor and bind to exposed hydrophobicity in newly synthesized proteins and assist them in folding or targeting to cellular membranes for insertion. However, proteins can be misfolded or mistargeted, which often causes hydrophobic amino acids to be exposed to the aqueous cytosol. Again, chaperones recognize exposed hydrophobicity in these proteins to prevent nonspecific interactions and aggregation, which are harmful to cells. The chaperone-bound misfolded proteins are then decorated with ubiquitin chains denoting them for proteasomal degradation. It remains enigmatic how molecular chaperones can mediate both maturation of nascent proteins and ubiquitination of misfolded proteins solely based on their exposed hydrophobic signals. In this review, we propose a dynamic ubiquitination and deubiquitination model in which ubiquitination of newly synthesized proteins serves as a “fix me” signal for either refolding of soluble protein.

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.