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

Abstract

Autophagy is responsible for the lysosomal degradation of proteins, organelles, microorganisms and exogenous particles. Epidermis primarily consists of keratinocytes which functions as an extremely important barrier. Investigation on autophagy in keratinocytes has been continuously renewing, but is not so systematic due to the complexity of the autophagy machinery. Here we reviewed recent studies on the autophagy in keratinocyte with a focus on interplay between autophagy machinery and keratinocytes biology, and novel autophagy regulators identified in keratinocytes. In this review, we discussed the roles of autophagy in apoptosis, differentiation, immune response, survival and melanin metabolism, trying to reveal the possible involvement of autophagy in skin aging, skin disorders and skin color formation. Since autophagy routinely plays a double-edged sword role in various conditions, its functions in skin homeostasis and potential application as a therapeutic target for skin diseases remains to be clarified. Furthermore, more investigations are needed on optimizing designed strategies to inhibit or enhance autophagy for clinical efficacy.

Keywords: autophagy; autophagy-related gene; keratinocyte; skin; skin disease.

Figure 1. Canonical and non-canonical autophagy pathway in keratinocytes

In response to changes of nutrients, energy and intracellular calcium and calmodulin, LKB1 and CaMK activate AMPK following direct modulation of downstream TSC2, raptor and ULK1. The mTOR inhibited by TSC2 or p18 is accompanied with inhibited p70S6K. Beclin1 promoting autophagy process while is inhibited through its bindings with Bcl2 or Mcl-1. ATG5–ATG12–ATG16L1 complex and LC3-II engage in the process from initiation of phagophore elongation to autophagosome formation. The iASPP depletion represses Mcl-1 or promotes ATG5–ATG12–ATG16L1 action. Armus promotes initiation of phagophore which could be blocked by Rac1. Rab9 could be assembled to double-membrane vesicles independently of ATG5/ATG7 and LC3. FGF7-FGFR2 signal stimulates the processes of formation and turnover of autophagosomes. BNIP3 promotes autophagy process but without recognized molecular target yet.

Figure 2. Autophagy machinery in melanin metabolism event

Pigmented melanosomes originated in melanocytes are transferred into neighboring keratinocytes, and the entering process is related to activation of FGF7-FGFR2 signal. UV radiation promotes FGFR2 internalization, and subsequent degradation of FGFR2 by autophagosomes/autolysosomes would ease autophagy capacity to degrade melanosomes.

Figure 3. Autophagy machinery in immune response in keratinocytes

Activated TLR2/6 and TLR4 led to increased p62 and activated autophagy through generation of ROS, MyD88 and TRAF6. The p62 promotes inflammatory cytokine generation via NF-κB. EGFR or KGFR is in charge of sensing stimulation from HPVs. HPV virus bind to heparan-sulfonated proteoglycans of cell surface and move to EGFR or KGFR following activation of downstream PI3K/Akt/mTOR pathway. During transport HPVs undergo Rab5 association. PFT induces autophagy with a possible target of AMPK. PAT treatment inhibits autophagosome degradation.