The Autophagy-Lysosomal Pathways and Their Emerging Roles in Modulating Proteostasis in Tumors

Abstract

In normal physiological condition, the maintenance of cellular proteostasis is a prerequisite for cell growth, functioning, adapting to changing micro-environments, and responding to extracellular stress. Cellular proteostasis is maintained by specific proteostasis networks (PNs) to prevent protein misfolding, aggregating, and accumulating in subcellular compartments. Commonly, the PNs are composed of protein synthesis, molecular chaperones, endoplasmic reticulum (ER), unfolded protein response (UPR), stress response pathways (SRPs), secretions, ubiquitin proteasome system (UPS), and autophagy-lysosomal pathways (ALPs). Although great efforts have been made to explore the underlying detailed mechanisms of proteostasis, there are many questions remain to explore, especially in proteostasis regulated by the ALPs. Proteostasis out-off-balance is correlated with various human diseases such as diabetes, stroke, inflammation, hypertension, pulmonary fibrosis, and Alzheimer's disease. , enhanced regulation of PNs is observed in tumors, thereby indicating that proteostasis may play a pivotal role in tumorigenesis and cancer development. Recently, inhibitors targeting the UPS have shown to be failed in solid tumor treatment. However, there is growing evidence showing that the ALPs play important roles in regulation of proteostasis alone or with a crosstalk with other PNs in tumors. In this review, we provide insights into the proteostatic process and how it is regulated by the ALPs, such as macroautophagy, aggrephagy, chaperone-mediated autophagy, microautophagy, as well as mitophagy during tumor development.

Keywords: aggregates; aggrephagy; autophagy-lysosomal pathways; chaperones; protein misfolding; proteostasis; proteostasis networks; tumors.

Figure 1

Proteostasis networks (PNs) in the cells. The proteostasis in a cell is regulated by protein synthesis, chaperones, unfolded protein responses (UPRs), stress response pathway (SRPs), ubiquitin proteasome system (UPS), autophagy-lysosomal pathways (ALPs), and secretions.

Figure 2

The autophagy-lysosomal pathways (ALPs) in the regulation of proteostasis. The ALPs are composed of macroautophagy, chaperone-mediated autophagy, aggrephagy, mitophagy, and microphagy. Abbrreviations: IsMI, lysosomal microautophagy; lesMI, late endosomal selective microautophagy; lebMI, late endosomal bulk microautophagy; CMA, chaperone-mediated autophagy; MT, microtubule; MTOC, microtubule organizing center; HECT, homologous to the E6-AP carboxyl terminus; RING, really interesting new gene; RBR, RING-betweenRING-RING; TRAF6, TNF receptor associated factor 6; p97/VCP, valosin containing protein; FAT10/UBD, ubiquitin D; CK II, casein kinase II; p62/SQSTM1, sequestosome 1; TRIM50, tripartite motif containing 50; HDAC6, histone deacetylase 6; BAG3, Bcl2-associated athanogene 3; GFAP, glial fibrillary acidic protein; LAMP-2A, lysosomal associated membrane protein 2; NBR1, neighbor of BRCA1 gene 1; OPTN, optineurin;NDP52, nuclear domain 10 protein 52; ULK1, Unc-51 like autophagy activating kinase 1; DFCP1, double FYVE-containing protein 1; WIPI1, WD repeat domain, phosphoinositide interacting 1; LC3, microtubule associated protein 1 light chain 3 alpha; PI3P, phosphatidylinositol 3-phosphate; GABARAP, gamma-aminobutyric acid receptor-associated protein; PINK1, PTEN induced putative kinase 1; Parkin, parkin RBR E3 ubiquitin protein ligase; MVBs, multivesicular bodies; ALFY, autophagy-linked FYVE-domain containing protein; VDAC1, voltage dependent anion channel 1; RAB7, Ras-related protein 7; RAB11, Ras-related protein 11; ESCRT I/III, endosomal sorting complex required for transport I/III; USP30, ubiquitin specific peptidase 30; PARL, presenilin associated rhomboid like; HTRA2, HtrA serine peptidase 2.