The ability to balance the amount of cellular components, remove damaged entities and recycle molecules by controlled degradation is crucial for cellular function and homeostasis. Lysosomes play a central role by acting as a major hub for degrading proteins, polysaccharides and lipids delivered by autophagy and endocytosis. This is mediated by various hydrolases, specifically acting in the acidic environment maintained in the lysosomal lumen. The lysosomal degradation chamber is isolated from the rest of the cell by a lipid bilayer containing numerous membrane proteins, which are coordinating the functions of lysosomes in processes such as cell homeostasis, metabolism, signalling and stress responses. The membrane proteins themselves are protected on the luminal side by glycosylation, which is key to lysosomal integrity.

But what if the lysosomes themselves become damaged or dysfunctional? Particularly ruptured lysosomes pose a serious threat to the cell, as leakage of luminal content into the cytoplasm can result in lysosome-mediated cell death. Lysophagy is a process by which irreparable lysosomes are degraded by selective autophagy (Henn, 2025). Upon lysosomal damage, cytosolic constituents gain access to the lumenal side of the lysosome, which allows ubiquitin-ligases and galectins to bind to exposed β-galactosides on lysosomal membrane proteins. This leads to ubiquitination of several lysosomal membrane proteins, including LAMP1, LAMP2 and TMEM192 (Figure). Autophagic adaptor proteins then bind to ubiquitin and galectins on the lysosomal membrane, and recruit the autophagic machinery.

Recently, a search for regulators of lysophagy in human cells identified a set of key players in one of several regulatory axes for this pathway (Pied, 2022). The first step in this particular cascade is the recruitment and phosphorylation of the serine/threonine kinase TBK1, which has previously been implicated as a sensor of membrane damage. TBK1 subsequently recruits and phosphorylates FBXO3, the substrate recognition component of the SCF-type E3 ubiquitin ligase complex SCF(FBXO3), which then ubiquitinates the lysosomal membrane protein TMEM192. Both activated TBK1 and SCF(FBXO3) can be found specifically at damaged lysosomes. Ubiquitinated TMEM192 is then recognized by the autophagic adaptor protein TAX1BP1, thus targeting damaged lysosomes for degradation. This sheds new light on the important regulation of lysophagy and offers potential targets for therapeutic interventions for diseases associated with lysosomal dysfunction, including lysosomal storage disorders (LSDs), neurodegenerative disorders and cancer.