Winner of the 2016 Louis-Jeantet Prize for Medicine

Born in 1957 in Naples, Italy, Andrea Ballabio studied Medicine at the Federico II University in Naples and took residency in Pediatrics at the same university. He was a post-doctoral fellow at Guy’s Hospital in London, UK, and then at the International Institute of Genetics and Biophysics in Naples, Italy. He spent many years in the US where he became Associate Professor at the Department of Molecular and Human Genetics, Baylor College of Medicine, and Co-Director of the Baylor Human Genome Center, in Houston, Texas. In 1994 he moved back to Italy to become director and founder of the Telethon Institute of Genetics and Medicine (TIGEM), a flagship institute for the study of rare genetic diseases, which is managed by the Italian Telethon Foundation. He is currently also Professor of Medical Genetics at the Federico II University in Naples and Visiting Professor at both Baylor College of Medicine, and at the University of Oxford, UK.

Andrea Ballabio has received many awards and recognitions for his work. He was President of the European Society of Human Genetics, Council member of the European Molecular Biology Organization (EMBO). In 2007, the President of the Italian Republic appointed him Knight of the Order of Merit. He received the European Society of Human Genetics International Award (2007) and the Advanced Investigator Award of the European Research Council (2010). In 2006, he was Torchbearer at the XX Torino Olympic Winter Games.

An “orchestra conductor” for the lysosomes

Lysosomes, cellular organelles discovered by the Noble Prize winner Christian de Duve, are the central core of the machinery that cleans the cell by degrading and recycling materials produced by cell metabolism. Until recently lysosomes have been considered as cellular “waste bags” and the terminal end of cell metabolic pathways. Andrea Ballabio challenged this dogma and demonstrated that lysosomes act as signalling hubs regulating pathways that control fundamental cellular processes in response to environmental cues.

Andrea Ballabio’s group discovered a master gene, TFEB, which controls the activity of lysosomes. This gene acts as an “orchestra conductor” regulating the expression of many other genes involved in the clearance of materials derived from cell metabolism. As defects in lysosomal function lead to common neurodegenerative diseases, as well as many rare inherited ones, the discovery of this novel biological pathway provides a promising therapeutic tool for disorders arising from the accumulation of pathological substrates.

Shorten and reproduced with permission from EMBO Molecular Medicine. Ballabio A (2016) “The awesome lysosome”. EMBO Mol Med doi:10.15252/emmm.201505966

The awesome lysosome

Running title: The lysosome in cell metabolism and disease

Keywords: autophagy, lysosomal storage diseases, mTORC1, TFEB, signalling

Andrea Ballabio

Telethon Institute of Genetics and Medicine (TIGEM), and Medical Genetics, Department of Translational Medicine, Federico II University, Naples, Italy;

Department of Molecular and Human Genetics, Baylor College of Medicine, and Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, USA.

E.Mail: ballabio(at)

The lysosome at a glance

Cellular organelles enable the spatial clustering of molecules, thus favoring their interactions in microenvironments ideally suited for specific complex functions. A well-known function of the lysosome is to degrade and recycle cellular waste. Extracellular materials reach the lysosome mainly through endocytosis and phagocytosis, whilst a completely
different process, autophagy, mediates
the delivery of intracellular
materials. Autophagy is activated by a broad range of cellular stress-inducing conditions and mediates the degradation of protein aggregates, oxidized lipids, damaged organelles and intracellular pathogens. The process typically involves the formation of double membrane-bound vesicles, the autophagosomes, which sequester cytoplasmic material and then fuse with lysosomes. Materials that reach the lysosome are degraded by lysosomal hydrolases and the resulting breakdown products are used to generate new cellular components and energy in response to the nutritional needs of the cell. Lysosomes are also involved in an “unconventional” secretory pathway known as lysosomal exocytosis, which plays an important role in various physiological processes such as plasma membrane repair, immune response, and bone resorption.

The lysosomal lumen has an acidic pH
close to 4.5 and contains approximately 60 different soluble hydrolytic
enzymes, which are
directly involved in the degradation of metabolites. The lysosomal membrane contains proteins such as, transporters, ion channels and SNAREs that mediate different aspects of lysosomal function, as well as the vATPase complex that mediates lysosomal acidification. In addition to lumenal and integral membrane proteins, an expanding number of proteins and of protein complexes have been found to associate, under particular conditions, to the lysosomal surface. The activity of such proteins may be either directly influenced by the lysosome, or, in turn may regulate or mediate specific aspects of lysosomal function. Notable examples are the mTORC1 kinase complex, whose activity depends on lysosomal nutrient content (Zoncu et al, 2011) and the BORC protein complex, which regulates lysosome positioning (Pu et al, 2015). We know however, the precise function of only a small fraction of the known lysosomal proteins and it is likely that additional ones remain to be identified.

The expanding role of the lysosome in human diseases

Mutations in genes encoding proteins involved in lysosomal function cause Lysosomal Storage Diseases (LSDs), a group of about 50 inherited disorders characterized by the progressive accumulation of undegraded substrates inside the lysosome. Patients with LSDs present with a debilitating, multi-systemic phenotype often associated with early-onset neurodegeneration. Unfortunately, therapeutic options are still inefficient or simply unavailable for most LSDs. How exactly the storage of undegraded material in LSDs causes cellular and tissue dysfunction and clinical symptoms has yet to be fully elucidated. A common consequence of pathological lysosomal storage is an impairment of autophagy, which leads to the secondary accumulation autophagy substrates.
Notably, the lysosome has also been found to be crucially involved in a variety of common disease conditions, such as neurodegenerative diseases, infection, obesity and cancer. Induction of the lysosomal-autophagic pathway was detected in pancreatic cancer (Perera et al, 2015). Furthermore, cancer cells were found to be more prone to lysosomal membrane permeabilization (Aits & Jaattela, 2013). In recent years, lysosomal gene mutations have been identified in an increasing number of patients with common neurodegenerative diseases, such as Parkinson’s and Alzheimer’s. For example, heterozygosity for mutations in the gene encoding glucocerebrosidase predisposes to Parkinson’s disease (Sidransky et al, 2009) via a mechanism that is still unclear. Interestingly, homozygosity for mutations in the same gene causes Gaucher disease, the most common neurodegenerative LSD.
Additionally, aggregate-prone proteins such as huntingtin and -synuclein that are involved in Huntington’s and Parkinson’s diseases, respectively, are degraded by the lysosomal-autophagic pathway and can be eliminated by inducing autophagy. These findings emphasize the importance of the lysosomal-autophagic pathway in neurodegenerative diseases and that therapeutic strategies aimed at rescuing and/or enhancing this pathway may have a broad impact on human health.

TFEB and the CLEAR network regulate lysosomal biogenesis

How the cell controls lysosomal function has remained unanswered and unexplored for a long time. A systems biology approach led to the discovery that lysosomal biogenesis and autophagy are transcriptionally regulated by a gene network, named CLEAR, and by its master gene TFEB (Sardiello et al, 2009; Settembre et al, 2011), a member of the Helix-Loop-Helix (HLH) leucine zipper family of transcription factors, providing the first evidence that lysosomal function is globally regulated and how this might occur.
We now know that TFEB plays a fundamental role in cell homeostasis and provides us with an unprecedented tool to globally induce lysosomal function and autophagy in in vitro, as well as in vivo. Overexpression of TFEB reduces the amount of accumulated substrates via the induction of the lysosomal-autophagic pathway. These include LSDs but also α1anti-trypsin deficiency and Spinal Bulbar Muscular Atrophy, as well as common diseases such as Parkinson’s, Alzheimer’s, and Huntington’s. In all cases TFEB overexpression resulted in a significant rescue of the disease phenotype (Settembre et al, 2013). Recent studies showed that another HLH transcription factor highly homologous to TFEB, TFE3, regulates a similar set of genes and is able to promote cellular clearance (Martina et al, 2014). The possibility of globally modulating lysosomal function by acting on TFEB/TFE3 and on the CLEAR network may lead to a novel therapeutic strategy with potential applicability to many diseases.

The lysosome as a signalling hub

The kinase complex mTORC1 (Mechanistic Target of Rapamycin Complex 1), a master controller of cell and organism growth, was recently shown to exert its activity on the lysosomal surface and to become inactive when released from the lysosome (Zoncu et al, 2011). mTORC1 belongs to a complex signalling machinery that responds to the lysosomal amino acid content via a nutrient sensing mechanism. Thus, the lysosome plays an important and unexpected role in cell signaling by controlling the activity of mTORC1.
Interestingly, mTORC1 regulates TFEB subcellular localization and activity. mTORC1-mediated phosphorylation of TFEB specific serine residues, which occurs on the lysosomal surface (Martina et al, 2012; Roczniak-Ferguson et al, 2012; Settembre et al, 2012), keeps TFEB inactive in the cytoplasm. Under nutrient-rich conditions active mTORC1 promotes biosynthetic pathways and blocks autophagy. A variety of stress stimuli, such as starvation and lysosomal stress, inhibit mTORC1 activity, thus inducing TFEB nuclear translocation and promoting lysosomal biogenesis and autophagy.
In addition, under energy demanding conditions, such as starvation and physical exercise, lysosomal calcium release via the lysosomal calcium channel mucolipin1 (MCOLN1) activates the calcineurin phosphatase, which in turn dephosphorylates TFEB, thus promoting its nuclear translocation and activation (Medina et al, 2015). Therefore, a lysosome-to-nucleus signaling mechanism enables lysosomal function to respond to environmental cues and regulates the switch between cellular biosynthetic and catabolic pathways (Settembre et al, 2012). These studies indicate that the lysosome acts as a signalling hub that controls cell metabolism and homeostasis.

The “lysosomics” approach

After 60 years from its discovery the lysosome has yet to reveal all its secrets. Future studies may reveal the presence of additional lysosomal regulatory networks operating at the transcriptional, post-transcriptional (e.g. microRNAs), or post- translational levels. An example of a lysosomal post-translational regulatory pathway is the regulation of sulfatases by the Sulfatase Modifying Factor 1 (SUMF1).
Lysosomal function may also be mediated by protein networks via protein-protein interactions. A few examples of such complexes have already been identified, such as the GLB1-NE1-GALNS-CTSA complex in the lysosomal lumen and the above- mentioned vATPase complex on the lysosomal membrane. Proteomic studies applied to the lysosome may reveal additional examples of such protein complexes and their function.
Another important goal is to further elucidate the signalling pathways that control lysosomal function as well as the role of the lysosome as a signalling hub. The study of these pathways may lead to the discovery of tools able to modulate lysosomal function in a sensitive and selective fashion. Functional genomic approaches (e.g. siRNA-based) and drug screenings, combined with high content cell-based assays, will play an important role in this endeavour.
Finally, we need to further define the role of lysosomal mutations as predisposing factors for human diseases. Whole genome, exome, and targeted sequencing of lysosomal genes, combined with functional analysis, may lead to the identification of new lysosomal genes whose mutations represent major determinants of the pathogenesis of a broad variety of human diseases. The Lysoplex tool (Di Fruscio et al, 2015) represents an example of a lysosome-targeted sequencing platform, which may be used to find both disease-causing mutations in LSDs and predisposing mutations in common diseases.

In conclusion, the biology and pathophysiology of the lysosome is still far from being completely understood. The integration of “omics” technologies to study the lysosome, an approach that may be termed “lysosomics”, will reveal the full potential of the awesome lysosome.

figure 1

Figure 1
A lysosome-to-nucleus signalling mechanism.
Signalling mechanisms that regulate TFEB nuclear translocation. Under normal feeding conditions, TFEB is phosphorylated by mTORC1 on the lysosomal surface and is sequestered in the cytoplasm by 14-3-3 proteins. During starvation and physical exercise MTORC1 is inactivated and Ca2+ is released from the lysosome through
MCOLN1. This leads to local calcineurin activation and TFEB dephosphorylation. Dephosphorylated TFEB
is no longer able to bind 14-3-3 proteins and can freely translocate to the nucleus where it transcriptionally activates the lysosomal/autophagic pathway [modified from (Medina et al, 2015)].


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Embo Molecular Medicine

Professor Andrea Ballabio

Telethon Institute of Genetics and Medicine (TIGEM)
Via Campi Flegrei 34
80078 Pozzuoli (Napoli)

Telephone: +39.081.6132207207
Fax: +39.081.5790919