Lysosome: The metabolic signaling hub

Abstract

For the past five decades the lysosome has been characterized as an unglamorous cellular recycling center. This notion has undergone a radical shift in the last ten years, with new research revealing that this organelle serves as a major hub for metabolic signaling pathways. The discovery that master growth regulators, including the protein kinase mTOR (mechanistic Target Of Rapamycin) make their home at the lysosomal surface has generated intense interest in the lysosome’s key role in nutrient sensing and cellular homeostasis. The transcriptional networks required for lysosomal maintenance and function are just being unraveled and their connection to lysosome-based signaling pathways revealed. The catabolic and anabolic pathways that converge on the lysosome connect this organelle with multiple facets of cellular function; when these pathways are deregulated they underlie multiple human diseases, and promote cellular and organismal aging. Thus, understanding how lysosome-based signaling pathways function will not only illuminate the fascinating biology of this organelle but will also be critical in unlocking its therapeutic potentials.

Immunometabolism in the development of rheumatoid arthritis

“…If there is ample nutrient supply, mTORC1 promotes cell growth by stimulating biosynthetic pathways, including synthesis of proteins, lipids, and nucleotides, and by inhibiting cellular catabolism through repression of the autophagic pathway . Colocalization of AMPK and mTORC1 on the lysosomal surface allows for direct cross‐regulation of AMPK and mTORC1, which share the lysosomal v‐ATPase‐Ragulator complex as an activator.…”

“…In RA CD4 T cells, AMPK lacks a lipid tail, fails to relocate to the lysosomal surface, and malfunctions as an mTORC1 inhibitor. AMPK deficiency promotes mitochondrial restraint and confers continuous mTORC1 activity of AMPK and mTORC1,79,80 which share the lysosomal v-ATPase-Ragulator complex as an activator.Analysis of AMPK recruitment to the lysosomal membrane has demonstrated low amounts of lysosomal AMPK in RA T cells, ex-plaining the persistent mitochondrial underperformance despite energy deficiency(Figure 7). Lysosomal anchoring of AMPK requires the addition of the C14-fatty acid myristic acid to the kinase's beta chain, accomplished by N-myristoyltransferase 1 (NMT1) 81,82.…”

Sepsis-associated Pathways Segregate Cancer Groups

“…Interestingly cancer cells are known to have increased biogenesis of lysosomes with different membrane composition, enhanced expression, activity and secretion of lysosomal enzymes [19]. Besides, Lysosomes are now considered as hub of metabolic signaling [20]. In our study, all members of SLC (except KIRC with non-significant positive ES) and SS groups have positive ES along with the UCEC, KIRP, THCA, BLCA and BRCA of the CA group ( Figure 3).…”

The antibiotic bedaquiline activates host macrophage innate immune resistance to bacterial infection

“…Lysosomes are both digestive organelles of the endocytic and autophagic pathways and signaling hubs involved in nutrient sensing, cell growth and differentiation, transcriptional regulation, and metabolic homeostasis (Lamming and Bar-Peled, 2019; Lawrence and Zoncu, 2019). In response to nutrients and growth factors, the mechanistic target of the rapamycin complex 1 (mTORC1) is recruited and activated at the lysosomal surface, where it promotes ribosomal biogenesis, translation, and biosynthesis of lipids (Lamming and Bar-Peled, 2019; Lawrence and Zoncu, 2019). mTORC1 binds to and phosphorylates TFEB, resulting in its cytosolic sequestration (Roczniak-Ferguson et al, 2012; Settembre et al, 2012).…”

“…mTORC1 binds to and phosphorylates TFEB, resulting in its cytosolic sequestration (Roczniak-Ferguson et al, 2012; Settembre et al, 2012). Upon starvation or lysosomal stress, mTORC1 is released from the lysosomal membrane and becomes inactive (Lamming and Bar-Peled, 2019; Lawrence and Zoncu, 2019). The release of lysosomal Ca 2+ activates the phosphatase calcineurin, which de-phosphorylates TFEB and promotes its nuclear translocation (Medina et al, 2015).…”