Lysosomes: multifunctional compartments ruled by a complex regulatory network

Abstract

More than 50 years have passed since Nobel laureate Cristian de Duve described for the first time the presence of tiny subcellular compartments filled with hydrolytic enzymes: the lysosome. For a long time, lysosomes were deemed simple waste bags exerting a plethora of hydrolytic activities involved in the recycling of biopolymers, and lysosomal genes were considered to just be simple housekeeping genes, transcribed in a constitutive fashion. However, lysosomes are emerging as multifunctional signalling hubs involved in multiple aspects of cell biology, both under homeostatic and pathological conditions. Lysosomes are involved in the regulation of cell metabolism through the mTOR/TFEB axis. They are also key players in the regulation and onset of the immune response. Furthermore, it is becoming clear that lysosomal hydrolases can regulate several biological processes outside of the lysosome. They are also implicated in a complex communication network among subcellular compartments that involves intimate organelle‐to‐organelle contacts. Furthermore, lysosomal dysfunction is nowadays accepted as the causative event behind several human pathologies: low frequency inherited diseases, cancer, or neurodegenerative, metabolic, inflammatory, and autoimmune diseases. Recent advances in our knowledge of the complex biology of lysosomes have established them as promising therapeutic targets for the treatment of different pathologies. Although recent discoveries have started to highlight that lysosomes are controlled by a complex web of regulatory networks, which in some cases seem to be cell‐ and stimuli‐dependent, to harness the full potential of lysosomes as therapeutic targets, we need a deeper understanding of the little‐known signalling pathways regulating this subcellular compartment and its functions.

Innovation and renovation: FEBS Open Bio in 2023

“…Jonathan Martinez‐Fabregas, a member of the journal's EAB, served as a guest editor of our special lysosomes issue. This issue contained five Review articles focussed on the important role of lysosomes, once thought to be little more than waste disposal units, in health and disease: in their article, Jonathan Martinez‐Fabregas, Irene Díaz‐Moreno and colleagues indicated that the lysosome is part of a complex communication network between organelles, and lysosome dysfunction is linked to a variety of pathologies [ 1 ]. These disease states include cancer and neurodegeneration, as reviewed by Janko Kos and co‐authors in the same issue [ 2 ].…”

A new glance at autophagolysosomal-dependent or -independent function of transcriptional factor EB in human cancer

“…The mammalian target of rapamycin complex 1 (mTORC1) plays a central role in sensing the cellular state and regulating TFEB activation [42,63,69]. The mTORC1/TFEB axis responds to various stimuli in the microenvironment, regulates several aspects of the cellular physiology, and coordinates lysosomal biogenesis and autophagy [63,70].…”

“…In addition, other regulators, such as members of the MITF family, AMPK, Wnt, p53, PtdIns3P, microRNAs/miRNAs, etc., function in autophagy [39][40][41]. Lysosomes are regulated by a sophisticated system to meet cellular needs when the microenvironment changes; that is, they have multiple functions, and lysosomal proteins are not merely constitutively transcribed from housekeeping genes [42]. Because lysosomes and autophagy machinery are both sophisticated and intimately related, the number of studies directed to the core regulators of the autophagolysosomal system is constantly increasing.…”