Lysosome biogenesis in health and disease

Abstract

This review focuses on the pathways that regulate lysosome biogenesis and that are implicated in numerous degenerative storage diseases, including lysosomal storage disorders and late-onset neurodegenerative diseases. Lysosomal proteins are synthesized in the endoplasmic reticulum and trafficked to the endolysosomal system through the secretory route. Several receptors have been characterized that execute post-Golgi trafficking of lysosomal proteins. Some of them recognize their cargo proteins based on specific amino acid signatures, others based on a particular glycan modification that is exclusively found on lysosomal proteins. Nearly all receptors serving lysosome biogenesis are under the transcriptional control of transcription factor EB (TFEB), a master regulator of the lysosomal system. TFEB coordinates the expression of lysosomal hydrolases, lysosomal membrane proteins, and autophagy proteins in response to pathways sensing lysosomal stress and the nutritional conditions of the cell among other stimuli. TFEB is primed for activation in lysosomal storage disorders but surprisingly its function is impaired in some late-onset neurodegenerative storage diseases like Alzheimer's and Parkinson's, because of specific detrimental interactions that limit TFEB expression or activation. Thus, disrupted TFEB function presumably plays a role in the pathogenesis of these diseases. Multiple studies in animal models of degenerative storage diseases have shown that exogenous expression of TFEB and pharmacological activation of endogenous TFEB attenuate disease phenotypes. These results highlight TFEB-mediated enhancement of lysosomal biogenesis and function as a candidate strategy to counteract the progression of these diseases. This article is part of the Special Issue "Lysosomal Storage Disorders".

Keywords: TFEB; autophagy; lysosomal biogenesis; lysosomal storage disorders; neurodegenerative disease; sorting receptors.

Conflict of interest statement

Conflict of interest

The authors declare no conflict of interest.

© 2018 International Society for Neurochemistry.

Figures

Figure 1.

Phosphorylation of TFEB by serine/threonine protein kinases. mTORC1, Akt, GSK3β and MAP4K3 phosphorylate TFEB at various serine residues. The positions of the phosphorylated residues refer to the human TFEB protein.

Figure 2.

Regulation of the synthesis and trafficking of lysosomal enzymes. TFEB modulates the expression of various lysosomal enzymes and of their transporters: LIMP-2 (SCARB2), sortilin (SORT1), and the mannose-6-phosphate (M6P) receptors (M6PR and IGF2R). TFEB also modulates the expression of a subunit of GlcNac-1-phosphotransferase (GNPTG) and of the uncovering enzyme (NAGPA), the Golgi-residing enzymes that generate the mannose-6-phosphate tags on most lysosomal enzymes.

Figure 3.

Interplay between TFEB and various molecular pathways in neurodegenerative disease. TFEB binding to CLEAR sites can be outcompeted by apoE4, a protein encoded by the Alzheimer’s disease risk factor APOE ε4 allele. TFEB mRNA levels can be decreased by miR-128, a microRNA that is upregulated in Alzheimer’s disease. Loss of functional presenilin in familial Alzheimer’s disease leads to increased phosphorylation of TFEB by mTORC1 and subsequent cytosolic sequestration by 14–3-3 proteins. Increased TFEB sequestration can also result from increased Akt/mTORC1 pathway activity downstream of iron accumulation. α-synuclein and polyQ-expanded androgen receptor (AR) also can sequester TFEB and decrease its action. Active TFEB promotes various lysosome-based clearance pathways that can counteract pathogenic storage of undegraded molecules in lysosomal storage disorders and proteinopathies.