Groundbreaking new research: Organelle contact regulation

New discovery of organelle contact regulation

A groundbreaking study has revealed how cellular compartments (organelles) control how they interact and cooperate

The research, led by Professor Michael Schrader and Dr Joseph Costello from the University of Exeter, builds on their recent discovery of two organelles - known as the peroxisome and the endoplasmic reticulum (ER).

This cooperation is critical for the production of specific lipids that are critical to nerve cell function and protect cells from oxidative damage

Organelles are the functional units of cells

For cells and organisms to survive, organelles must interact and cooperate

How this is mediated and regulated in cells is an important and challenging question in cell biology

In a previous study, the researchers found that a protein in the peroxisome called ACBD5 directly interacts with a protein in the endoplasmic reticulum called VAPB

This interaction links the two organelles together and allows lipid transfer between them

The new study sheds light on how this interaction is regulated at the molecular level

"Organelles don't always connect with each other, which would be disadvantageous," Professor Schreeder said

"They also need to keep their distance and change their position in the cell to encounter other organelles

Therefore, membrane contacts between organelles need to be dynamic

"Our findings reveal how the regulation of peroxisome-ER contacts works in mammalian cells and provide the first clear example of the physiological role of peroxisomal protein phosphorylation," Dr.

Phosphorylation reactions are key to many cellular processes in biology

The addition (or removal) of phosphate to a protein can alter its properties, thereby altering its function or activity

Therefore, protein phosphorylation/dephosphorylation is an important regulatory mechanism in cells
.

It is done by enzymes such as kinases, which mediate protein phosphorylation, and phosphatases, which remove phosphorylation (dephosphorylation)
.

The researchers found that a binding motif of ACBD5, called the FFAT motif, is required for interaction with the VAPB protein domain, and it can be phosphorylated at multiple amino acids
.

Notably, phosphorylation of only one amino acid in the core region of the FFAT motif prevents ACBD5 from binding to VAPB and inhibits peroxisome-ER membrane contact
.

In addition, the researchers discovered an enzyme, a kinase called GSK3β, that phosphorylates ACBD5 in cells
.

In addition, we identified other phosphorylation sites near the core region, and phosphorylation at these sites facilitated the ACBD5-VAPB interaction, revealing a complex regulatory mechanism
.

The researchers collaborated with the laboratory of Professor Bettina Warscheid at the University of Freiburg in Germany, an expert in phosphoproteomics
.

"The FFAT motif is found in many other proteins that are involved in VAP protein interactions elsewhere in the cell," Professor Schrader said
.

"Our findings extend current FFAT patterns and point to a general mechanism by which they are regulated by phosphorylation
.

"Understanding how they are regulated is also relevant to disease
.
"

ACBD5-deficient patients suffer from peroxisomal disease that severely damages the brain and retina, affecting vision, while VAPB and GSK3β have been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)
.

People with severe peroxisomal disease, also known as Zellweger spectrum disorder, often die in childhood or youth, the team collaborated with researchers from the Amsterdam Academic Medical Centre and a charity called Zellweger UK Agency experts collaborate to address peroxisomal disorders, raise awareness, and support families and patients
.

article title

Regulating peroxisome-ER contacts via the ACBD5-VAPB tether by FFAT motif phosphorylation and GSK3β