Enhanced translation expands the endo-lysosome size and promotes antigen presentation during phagocyte activation

Abstract

The mechanisms that govern organelle adaptation and remodelling remain poorly defined. The endo-lysosomal system degrades cargo from various routes, including endocytosis, phagocytosis, and autophagy. For phagocytes, endosomes and lysosomes (endo-lysosomes) are kingpin organelles because they are essential to kill pathogens and process and present antigens. During phagocyte activation, endo-lysosomes undergo a morphological transformation, going from a collection of dozens of globular structures to a tubular network in a process that requires the phosphatidylinositol-3-kinase-AKT-mechanistic target of rapamycin (mTOR) signalling pathway. Here, we show that the endo-lysosomal system undergoes an expansion in volume and holding capacity during phagocyte activation within 2 h of lipopolysaccharides (LPS) stimulation. Endo-lysosomal expansion was paralleled by an increase in lysosomal protein levels, but this was unexpectedly largely independent of the transcription factor EB (TFEB) and transcription factor E3 (TFE3), which are known to scale up lysosome biogenesis. Instead, we demonstrate a hitherto unappreciated mechanism of acute organelle expansion via mTOR Complex 1 (mTORC1)-dependent increase in translation, which appears to be mediated by both S6Ks and 4E-BPs. Moreover, we show that stimulation of RAW 264.7 macrophage cell line with LPS alters translation of a subset but not all of mRNAs encoding endo-lysosomal proteins, thereby suggesting that endo-lysosome expansion is accompanied by functional remodelling. Importantly, mTORC1-dependent increase in translation activity was necessary for efficient and rapid antigen presentation by dendritic cells. Collectively, we identified a previously unknown and functionally relevant mechanism for endo-lysosome expansion that relies on mTORC1-dependent translation to stimulate endo-lysosome biogenesis in response to an infection signal.

Changes in the Oligodendrocyte Progenitor Cell Proteome with Ageing

“…As lysosomes are key in maintaining neural stem cell quiescence ( 106 ), a dysregulation and accumulation of storage material in the cell that requires increase lysosome biogenesis ( 107 , 108 ) as occurs in neuronal lipofuscinosis, could signal OPC senescence. Thus, this change reflect an adaptation of the lysosome to changes in the energy state of aged OPCs or to a higher inflammatory environment, similar to that shown in activated phagocytes, cancer cells and other inflammatory diseases ( 109 , 110 , 111 ). These increases in lysosomes and autophagy could also be a cell-intrinsic compensatory mechanism in response to ageing cues ( 77 ).…”

Parkinson’s Disease–Associated LRRK2 Interferes with Astrocyte-Mediated Alpha-Synuclein Clearance

“…Lrrk2 GS/GS cells did not show any intensification of neural red staining suggesting a possible impairment in their ability to ingest extracellular α-syn. In phagocytes, it was recently reported that the endo-lysosomal compartment undergoes adaptation, remodeling, and expansion during particle internalization through an enhanced translation [87]. In this regard, our findings might suggest that striatal astrocytes harboring the G2019S mutation in Lrrk2 also fail to adapt and expand their endo-lysosomal system when they are stimulated to phagocytize, resulting in α-syn-defective internalization.…”

Phagosome resolution regenerates lysosomes and maintains the degradative capacity in phagocytes

“…This bolus of amino acids may be sensed by intraluminal amino acid sensors like the V-ATPase, or by cytoplasmic sensors like CASTOR, after amino acid transport across the phagolysosome membrane, locally promoting mTORC1 activation (Saxton et al, 2016; Chantranupong et al, 2016; Zoncu et al, 2011; Inpanathan and Botelho, 2019). While mTORC1 drives many anabolic processes like protein and lipid synthesis, mTORC1 also plays a role in coordinating phagosome and lysosome dynamics, including efferosome fission (Krajcovic et al, 2013; Inpanathan and Botelho, 2019; Saric et al, 2016; Hipolito et al, 2019). Thus, cargo degradation coupled to mTORC1 activation could help orchestrate phagosome resolution.…”

“…While mTORC1 drives many anabolic processes like protein and lipid synthesis, mTORC1 also plays a role in coordinating phagosome and lysosome dynamics, including efferosome fission (Krajcovic et al, 2013;Inpanathan and Botelho, 2019;Saric et al, 2016;Hipolito et al, 2019).…”