The role and the fame of the lysosomes in cell metabolism are mainly connected to their well-known activity of “garbage collectors”. They are plenty of hydrolytic enzymes that degrade different types of useless macromolecules, thus generating smaller, simpler basic molecules that can enter once again in the flow of the biochemical pathways of the cells.
The degradation role of the lysosomes is fundamental: more than 50 human diseases are directly related to the impairment of enzymes directly involved in the catabolism of the macromolecules. This class of diseases is known as “lysosomal storage disorders”, and some of them, like the Sanfilippo syndrome, are associated with neurological deficits.
In the last years, a great number of novel lysosomal proteins has been discovered. Many of them carry out a Signaling Function
Signaling function in lysosomes appear in two main ways, either a) responding to changes in nutrient availability and to the presence of growth factors nearby the lysosomes or b) going back and forth between the lysosomes and the nucleus – thus acting as transcription factors. When mutations affect genes encoding for these signalization proteins, many illnesses appear.
a) Referring to the first group of signalization proteins localized close to the lysosomes, mTORC1 has an important role. It interacts with many other proteins in response to variations in the energy content of the cell. It is activated when the cell disposes of a lot of energy (ATP, glucose, growth factors…), while decreases its activity in conditions of low energy, for example when the concentration of AMP increases.
In some cases, when one of the proteins involved in the signaling pathway does not fulfill its function, mTORC1 may become hyperactive, and gives cells a wrong signal of uncontrolled growth. Depending on which regulatory protein become dysfunctional, a large list of diseases has been discovered, many of them with neurological consequences: tuberous sclerosis complex, which may lead to epilepsy, cognitive impairment, and autism; migraine susceptibility; various types of cancer.
mTORC1 activity is also regulated by the intracellular concentration of amino acids; however, the exact mechanisms of this kind of interactions are not well understood yet. When the response to amino acids is impaired, other diseases arise. One of them, the Birt-Hogg-Dubé syndrome, is characterized by follicle tumors, renal carcinoma, collapse of lungs (pneumothorax), and lung cysts. Other known diseases associated with this kind of dysregulation are epilepsy, brain malformations, and abnormal neuron growth.
b) Moving to the group of proteins that move between the lysosomes and the nucleus, the transcription factor TFEB catches the focus of attention. In normal conditions, when the lysosomes work well, and in presence of an adequate level of nutrients, TFEB is not activated. However, in the case of an impairment of lysosomes’ function or some loss of intracellular amino acids, TFEB “switches on” and migrates from the lysosomes to the nucleus, where activates specific genes that allow the cell to adapt to the new conditions.
Once again, if transcription factors are either inactivated by a mutation or hyper-expressed by, for example, the proximity of a strong promoter, cell homeostasis is broken, and diseases arise. Two of the most frequent are the renal carcinoma and the melanoma; moreover, the Birt-Hogg-Dubé syndrome is also related to the disruption of the lysosomal transcription factors.
In conclusion, the discovery of lysosomal proteins involved in signalization pathways is widening the knowledge on the functions of the lysosomes. This can provide a better understanding of the causes of a number of diseases that were not related to these organelles so far. Nevertheless, the relation between the lysosomal storage of different types of molecules and their relations to the diseases – including neuropathologies – is still poorly understood.
MAIN MESSAGES
Lysosomes integrate signalization pathways via mTORC1. They also regulate the expression of genes through the activation of specific transcription factors. Mutations of signaling protein and transcription factors lead to the rise of neurological diseases and different types of cancer.
Reference:
Ferguson S.M. Beyond indigestion: emerging roles for lysosome-based signaling in human disease. Curr Opin Cell Biol. 2015 August; 35: 59–68. doi:10.1016/j.ceb.2015.04.014.
The elaboration of this post has been financed by the project PI15/01082, as a part of the National Plan of I+D+I and co-financed by the ISCIII – General Deputy Direction for Evaluation and Development of Health Research – and the European Regional Development Fund (ERDF).
