The lysosomal signaling anchor p18/LAMTOR1 controls epidermal development by regulating lysosome-mediated catabolic processes

Abstract

The lysosomal adaptor protein p18 is an essential anchor of a scaffolding complex for the mTORC1 and MAPK pathways, which play crucial roles in controlling cell growth and energy homeostasis. To elucidate the in vivo function of the p18-mediated pathway, we conditionally ablated p18 in the mouse epidermis. Mutant mice were born with severe defects in formation of the stratum corneum and died within 12 h after birth due to dehydration caused by loss of skin barrier function. Mutant epidermal cells can grow and differentiate into granular cells, but exhibit functional defects in corneocyte maturation. Electron microscopy identified abnormal immature cells, overlying the mutant granular cells, which accumulated autophagosomes, glycogen granules and dead nuclei. Cell culture analysis showed that loss of p18 attenuated lysosome function, resulting in accumulation of immature lysosomes and autophagosomes. Analyses of lysosome behavior revealed that p18 is required for functional interaction between lysosomes and target organelles including autophagosomes. These findings suggest that p18-mediated pathways control lysosome-mediated catabolic processes, which are crucial for the development of mouse epidermis.

The mTOR Pathway Controls Cell Proliferation by Regulating the FoxO3a Transcription Factor via SGK1 Kinase

“…To dissect the role of lysosomal mTORC1 in cell-cycle progression, we generated p18-knockout cells (p18KO) from p18 flox/flox MEFs [22] using an in vitro Cre-loxP system. We also prepared a revertant cell line that re-expresses p18 in p18KO cells (p18Rev), for use as a control.…”

“…p18 fl/fl mouse embryonic fibroblasts (MEFs) were established from a p18-floxed mouse [22]. p18 -/- cell lines were established by transfecting p18 fl/fl MEFs with an integrase-defective Cre vector, a gift from Dr. Masahito Ikawa.…”

“…One of these, p18, has a fatty-acyl modification and serves as an essential anchor of the complex to the lysosomal membrane. We previously identified p18 as a membrane anchor of the p14/MP1 complex on late endosomes/lysosomes [21], and subsequently showed that p18 plays a crucial role in regulating mTORC1 function in lysosome biogenesis and maturation processes [22], [23].…”

The signaling involved in autophagy machinery in keratinocytes and therapeutic approaches for skin diseases

“…The mTORC1 is speculated the target of p18 protein, a novel membrane adaptor. The p18-depleted epidermis exhibits severe defects on stratum corneum development and corneocyte formation, and these immature corneocyte-like cells displayed lots of autophagosomes [40]. Normal keratinocytes are of high autophagic activity, and the autophagosomes are rapidly degraded by fusion with lysosomes.…”

Depletion of p18/LAMTOR1 promotes cell survival via activation of p27kip1‐dependent autophagy under starvation

“…The p18 protein has originally been known as an adaptor to control endosome dynamics or lysosomal function by anchoring the MEK1-ERK pathway or the mTORC1 pathway via p14-MP1 complexes (Nada et al, 2009;Sancak et al, 2010). Recently, this protein has been suggested to regulate other intracellular trafficking processes to maintain cell homeostasis and development of particular cell types (Soma-Nagae et al, 2013). Since both ERK and mTORC1 pathways are required for cell survival and growth, p18 might involve in regulating cell viability under starvation via the regulation of ERK or mTORC1 pathway.…”