The regulated transcription of genes required for peroxisome biogenesis is the connection between cell signalling and peroxisome biology

The regulated transcription of genes required for peroxisome biogenesis is the connection between cell signalling and peroxisome biology. Combined biochemical fractionation and mass spectrometry approaches was used for studies to identify over 85 different proteins found in peroxisomes. However, enzymes that are involved in metabolic processes carried out by peroxisomes have been primarily identified, although mevalonate and phosphomevalonate kinase are classified as peroxisomal proteins. The first report about peroxisome as signalling organelles appear by Dixit et al. They demonstrated that besides mitochondria, mitochondrial antiviral signalling protein (MAVS)also localize at peroxisome and is crucial for antiviral innate immunity. The role of peroxisome in innate immune response was further expanded by the same group and it is reported that peroxisomes increases expression of type III interferon in response to diverse pathogenic stimuli.

Tuberous Sclerosis Complex 2 (TSC2) is a negative regulator of mammalian target of rapamycin complex 1 (mTORC1) signalling. GTPase activating protein (GAP) is formed by TSC2 and TSC1 and can be found in the endomembrane and regulates Ras homolog enriched in brain (Rheb), which is needed for mTORC1 signalling. On mTORC1 signalling, TSC1/2 works as a ‘brake’. AMP kinase (AMPK) phosphorylation in response to energy stress will activate TSC.TSC will be inactivated when TSC2 is phosphorylated by other kinases in response to growth factor signalling, such as protein kinase B(AKT). AKT creates a 14-3-3 binding site, which removes TSC2 from the membrane, isolating it in the cytosol and relieving inhibition of Rheb to inactivate TSC.
Ataxia telangiectasia mutated (ATM) is a kinase that repairs DNA and the ‘first responder’ to double-strand breaks in DNA. ATM triggers several downstream signalling cascades that start DNA repair, cell cycle arrest and apoptosis when activated by DNA damage. Other than regulating cellular reactive oxygen species (ROS) level, ATM is used for carbon metabolism, adipocyte differentiation and glucose homeostasis, insulin resistance, cardiac remodelling and induction of autophagy.
Cross-talk between signalling pathways in which the TSC-2 and ATM tumour suppressors participate requires peroxisomes. Oxidative stress causes cytoplasmic ATM to activate. ATM phosphorylated LKB in response to exogenous or endogenous ROS, and later reactive nitrogen species (RNS) to activate AMPK and TSC2. As a result, mTORC1 signalling was shut off, decreasing protein synthesis and activating autophagy. A new function for ATM in the cytoplasm was established and a new signalling pathway is identified in which both ATM and TSC2 participated to regulate autophagy in response to oxidative stress.

Soon, these early studies were followed by data that the TSC signalling node (TSC1, TSC2 and Rheb) was localized to the peroxisome. On TSC1 and TSC2, peroxisome targeting sequences were identified. If mutated, their localization to the peroxisome will be discontinued. Other data was about the TSC tumour suppressor will be activated by peroxisomal ROS when localized to the peroxisome, using drugs like fibrate Wy-14643, which triggers peroxisomes to produce more ROS. In the liver, Peroxisome proliferator-activated receptor (PPAR) activation by fibrates leads to an imbalance between PPAR-mediated transcription of peroxisomal ROS creating enzymes and ROS scavenging enzymes, causes the production of peroxisomal ROS increase. Hepatocarcinogenesis can occur due to this elevated ROS. Repression of mTORC1 occurred when TSC2 was activated by peroxisomal ROS, which increased autophagic flux in the cell.

The activation of the TSC tumour suppressor and specifically targets peroxisomes for pexophagy in response to ROS is mediated by ATM localization to the peroxisome. An initial report from the Watters group had localized ATM to the peroxisome, and identified a putative peroxisome import signal at the carboxyterminus of this kinase. ATM signals via LKB1 and AMPK to phosphorylate and activate TSC2, repressing mTORC1 and increasing autophagic flux when activated by peroxisomal ROS.