The Roles of Endo-Lysosomes in Unconventional Protein Secretion

Abstract

Protein secretion in general depends on signal sequence (also named leader sequence), a hydrophobic segment located at or close to the NH2-terminus of a secretory or membrane protein. This sequence guides the entry of nascent polypeptides into the lumen or membranes of the endoplasmic reticulum (ER) for folding, assembly, and export. However, evidence accumulated in recent years has suggested the existence of a collection of unconventional protein secretion (UPS) mechanisms that are independent of the canonical vesicular trafficking route between the ER and the plasma membrane (PM). These UPS mechanisms export soluble proteins bearing no signal sequence. The list of UPS cargos is rapidly expanding, along with the implicated biological functions, but molecular mechanisms accountable for the secretion of leaderless proteins are still poorly defined. This review summarizes our current understanding of UPS mechanisms with an emphasis on the emerging role of endo-lysosomes in this process.

Lysosomes as a therapeutic target

“…The accumulation of such undigested macromol ecules or monomers in LSDs instigates the formation of secondary products, which ultimately escape from the endosomal-autophagic-lysosomal pathways 9,71 and lead to multiple consequences that affect most organs, including the brain, liver, spleen, heart, eyes, muscles and bone (TABLe 2). Most, if not all, organelles are altered in LSDs, including endosomes, autophagosomes and lysosomes, and their functions in lysosomal formation/ reformation and fusion of endosomes or autophago somes to lysosomes are abnormal.…”

Mechanisms of secretion and spreading of pathological tau protein

“…Besides multivesicular bodies, tau may also be found in endo-lysosomes. Fusion of endo-lysosomes with the PM releases tau and other proteins to the extracellular space in a vesicle-free form [148]. Tau may be delivered to endolysosomes by multiple protein trafficking pathways.…”

“…Tau may be delivered to endolysosomes by multiple protein trafficking pathways. First, during cellular stress and overloading of the ubiquitin-proteasome clearing system, a misfolding-associated protein secretion pathway (MAPS) can be activated to translocate misfolded proteins, including tau, to endo-lysosomes for secretion to the extracellular space [148,149]. The MAPS pathway involves the initial capture of misfolded proteins by the chaperone ubiquitin carboxyl-terminal hydrolase 19 (USP19) at the extracellular surface of ER.…”

“…The MAPS pathway involves the initial capture of misfolded proteins by the chaperone ubiquitin carboxyl-terminal hydrolase 19 (USP19) at the extracellular surface of ER. Then, co-chaperones Hsc70 and DNAJC5 mediate the sorting of misfolded cargos into the lumen of endo-lysosomes [148,150]. Alternatively, dysfunctional cytoplasmic proteins and protein Compared to cellular tau aggregates can be delivered to endo-lysosomes through macroautophagy [148].…”

“…Then, co-chaperones Hsc70 and DNAJC5 mediate the sorting of misfolded cargos into the lumen of endo-lysosomes [148,150]. Alternatively, dysfunctional cytoplasmic proteins and protein Compared to cellular tau aggregates can be delivered to endo-lysosomes through macroautophagy [148]. Several reports have suggested a role of macroautophagy in tau secretion [151][152][153][154].…”