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The lysosomal proteome of senescent cells contributes to the senescence-associated secretome

ABSTRACT: Senescent cells accumulate in tissues over time, favoring the onset and progression of multiple age-related diseases. The senescence-associated secretory phenotype (SASP) is considered the main pathological feature of senescent cells, however, little is known about the mechanism of secretion of SASP factors. Here, we report that human senescent cells present higher levels of the two main types of authophagy, namely macroautophagy (MA) and chaperone-mediated autophagy (CMA), together with an increase in the transcription factor TFEB and in lysosomal mass. Proteomic analyses showed profound and widespread changes in the composition of lysosomal substrates in both CMA- and MA-derived lysosomes. Notably, some proteins previously identified as plasma biomarkers of aging in humans are highly enriched in the lysosomes of senescent cells, as it is the case of cathepsin D (CTSD). Moreover, we found that senescent cells have the ability to perform lysosomal exocytosis in a RAB27A-dependent manner and this is the main route for the secretion of multiple cytokines (such as CCL2, CCL3, CXCL12), the protease inhibitor SERPINE1 and protease CTSD. We conclude that lysosomes are hyperactive in senescent cells, display an altered pattern of constitutive proteins and lysosomal substrates, and undergo exocytosis contributing to the SAS

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell

DISEASE(S): Cutaneous Malignant Melanoma 1

SUBMITTER: Fernando Garcia

LAB HEAD: Javier Muñoz Peralta

PROVIDER: PXD022492 | Pride | 2022-08-29

REPOSITORIES: Pride

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