One way for cells to regulate metabolic processes is to compartmentalise metabolic enzymes into distinct locations to modulate their access to substrates and co-factors. The peroxisome is one such compartment, and defects in peroxisome function have been associated with metabolic diseases. Now, Maya Schuldiner, Ralf Erdmann, Einat Zalckvar and co-workers (Gabay-Maskit et al., 2020) investigate the localisation and targeting of the budding yeast malate dehydrogenase 2 (Mdh2) to peroxisomes. They show that GFP-tagged Mdh2 localises to both the cytosol and peroxisomes. Moreover, using protease protection assays, they demonstrate that Mdh2 is found within the peroxisomal matrix, rather than at the periphery. To identify factors that are required for Mdh2 targeting to peroxisomes, the authors perform a screen of peroxisome-related genes and find that Mdh2 localisation to peroxisomes is perturbed in the absence of Pex5, a component of the peroxisomal-targeting machinery, and Mdh3, a peroxisomal iso-enzyme of Mdh2. Because Mdh2 does not contain a peroxisomal-targeting signal, the authors hypothesise that it may target to peroxisomes by piggybacking on Mdh3. Indeed, obstruction of the targeting signal of Mdh3 interferes with the efficient localisation of Mdh2 to peroxisomes. Together, these findings illustrate that compartmentalisation of metabolic enzymes can be achieved by a piggybacking mechanism, a finding that may become relevant for our understanding of metabolic disorders.
