Having a deeper understanding of peroxisomes can help move our understanding of immunity forward.
Peroxisomes are cell organelles that carry out a number of functions, including the degradation of cytotoxins. They have been a mystery to scientists for many years – but new research is starting to shed light on these multifunctional cells.
Peroxisomes are cell organelles of vital importance to cells as they provide an insulated reaction chamber for more than 50 different kinds of enzymes and are linked to different cellular processes. The main function of peroxisomes is the degradation of long-chain fatty acids and cytotoxins.
They are vital for highly specialised functions such as the synthesis of penicillin in fungi, the formation of lysine in yeasts, the photorespiration of plants and the generation of plasmalogens for the white matter of the brain in animals. Defects in the formation of functional peroxisomes lead to severe metabolic disorders in humans, which often result in infant death.
In order to degrade cytotoxins peroxisomes need enzymes that have to be transported into the peroxisomes via complicated machinery. The team from the research group Biochemistry of Intracellular Transport Mechanisms at Ruhr-Universität Bochum (RUB) headed by Professor Harald Platta has detected an as-yet unknown transport step, thus gaining a better understanding of life-threatening diseases.
The engine of the import machinery
In order for peroxisomes to fulfil their functions, they have to import the relevant enzymes inside first. Most enzymes are guided into the respective peroxisome by the import receptor Pex5p. That receptor is controlled by the protein ubiquitin (Ub) that attaches itself to the receptor temporarily.
Professor Platta said: “To date, we have been able to break down the import mechanism into five steps. First, the binding of Pex5p to the imported enzyme in the cytoplasm. Second, the binding of the Pex5p enzyme complex with the peroxisome. Third, the enzyme being released inside the peroxisome. Fourth, Ub attaching itself to Pex5p. And fifth, the export of Ub-modified Pex5p into the cytoplasm to enable further import reactions”.
The ABS of molecular machines
The attachment of a Ub molecule to Pex5p plays a crucial role for the import cycle. Energy is required for this step, as well as for the subsequent export of the complex. The current study, which is based in the first place on the PhD projects of Rebecca Brinkmeier and Fouzi El Magraoui, has provided an answer to this question. By analysing systematically generated Ub and Pex5p variants, the team demonstrated that a stable Ub-Pex5p fusion causes a defect in the peroxisomal protein import. Accordingly, Ub has to be detached from Pex5p again.
Once ubiquitin has been taken over by another enzyme, Pex5p reverts to its original status and can be reused. If this step is missing, the import receptor spins out of control. First, it careens inside the cytoplasm as a complex, until it erratically crashes back into the peroxisome where it blocks the docking complex, thus inhibiting the import of the correct Ub-modified Pex5p.
Professor Platta said: “Eventually, this leads to complete loss of function in the peroxisome”.
Peroxisomes fighting against bacterial infections
Another new study has shown that the organelle is required for the innate immune response to engulf and destroy bacteria. Previously, the organelle had no link to the immune response. University of Alberta researchers have found that peroxisomes are required for cells in the innate immune response to bacteria and fungi.
The discovery was first made in an unlikely place – in fruit flies. Research Associate Francesca Di Cara, Richard Rachubinski, professor and chair of the Department of Cell Biology, and Andrew Simmonds, cell biology associate professor, partnered up to create fruit flies that could be used specifically for studying peroxisomal disorders.
The researchers found that peroxisomes are necessary for proper functioning of the innate immune system, the body’s first line of defence against microorganisms, as well as communicating to other organs that there is an infection. The team discovered that when the organelle’s basic function is altered, this communication is lost and the organism does not fight the bacteria.
Di Cara said that: “Understanding how the body fights infection has an impact on human health. We have to understand who the ‘fighters’ in the organism are before we can identify what’s failing in the battle against bacterial infections.”
Peroxisomes are ‘chemical factories’ that process complex fat molecules into simple forms and modify reactive oxygen molecules, which together act to signal to cells and tissues to respond appropriately to changes in their environment.
Along with their collaborator Nancy Braverman from McGill University, the researchers used a mouse model to confirm that what they observed in the flies also occurred in a mammalian system.
Rachubinski said: “To find organelles like peroxisomes that had no link whatsoever to fighting bacterial infections was a critical discovery – it will help expand the roles of what this important organelle does in innate immunity against bacteria and fungi, and its involvement in viral signalling and the lethal peroxisome genetic diseases. As the threat of bacterial infections continues to grow, this discovery can help move our understanding of immunity forward.”