MERTK-Mediated LC3-Associated Phagocytosis (LAP) of Apoptotic Substrates in Blood-Separated Tissues: Retina, Testis, Ovarian Follicles

Abstract

Timely and efficient elimination of apoptotic substrates, continuously produced during one’s lifespan, is a vital need for all tissues of the body. This task is achieved by cells endowed with phagocytic activity. In blood-separated tissues such as the retina, the testis and the ovaries, the resident cells of epithelial origin as retinal pigmented epithelial cells (RPE), testis Sertoli cells and ovarian granulosa cells (GC) provide phagocytic cleaning of apoptotic cells and cell membranes. Disruption of this process leads to functional ablation as blindness in the retina and compromised fertility in males and females. To ensure the efficient elimination of apoptotic substrates, RPE, Sertoli cells and GC combine various mechanisms allowing maintenance of tissue homeostasis and avoiding acute inflammation, tissue disorganization and functional ablation. In tight cooperation with other phagocytosis receptors, MERTK—a member of the TAM family of receptor tyrosine kinases (RTK)—plays a pivotal role in apoptotic substrate cleaning from the retina, the testis and the ovaries through unconventional autophagy-assisted phagocytosis process LAP (LC3-associated phagocytosis). In this review, we focus on the interplay between TAM RTKs, autophagy-related proteins, LAP, and Toll-like receptors (TLR), as well as the regulatory mechanisms allowing these components to sustain tissue homeostasis and prevent functional ablation of the retina, the testis and the ovaries.

Zearalenone Promotes Uterine Hypertrophy through AMPK/mTOR Mediated Autophagy

“…In our experiments, the relative expression of Beclin1 in the endometrial epithelium increased linearly with increasing ZEN concentration, consistent with the transcriptomic results of the porcine endometrial epithelial cells in the in vitro model. LC3 is a specific autophagic marker that can reflect the strength of autophagy via both the number of autophagosomes and the level of LC3 lipid formation [ 21 ]. Research has shown that with the increase in ZEN, the expression of LC3-II increases linearly [ 16 , 46 ].…”

“…During apoptosis, internucleosomal DNA enters the vesicle and is engulfed by other cells [ 20 ]. Apoptotic cells are immediately eliminated by cells with phagocytic activity, avoiding the autoimmune response of the cells [ 21 ] and facilitating the stability of the tissue environment [ 22 ]. Thus, deep analysis of the mechanism of ZEN has become an important scientific problem.…”

Transcriptomic Changes Predict Metabolic Alterations in LC3 Associated Phagocytosis in Aged Mice

“…A sub-set of the autophagy related proteins are involved in a hybrid autophagy-phagocytosis pathway, termed LC3-associated phagocytosis (LAP), considered a non-cannonical autophagy pathway [ 8 , 9 , 10 , 11 , 12 ]. Professional phagocytes such as macrophages, monocytes, and dendritic cells, as well as non-professional/specialized phagocytes, such as mammary epithelial cells, retinal pigment epithelial (RPE) cells, and sertoli cells utilize LAP for optimal degradation of phagocytosed material, including dead cells/cellular debris, and to recycle nutrients, such as vitamin A derivatives [ 6 , 11 , 13 , 14 , 15 ]. While LAP shares molecular machinery with CA, it is a distinct process; unlike CA, LAP is AMPK–mTORC1–ULK1 independent and unresponsive to nutrient status [ 8 , 11 , 16 ].…”

Transcriptomic changes predict metabolic alterations in LC3 associated phagocytosis in aged mice

“…A sub-set of the autophagy related proteins are involved in a hybrid autophagy-phagocytosis pathway, termed LC3-associated phagocytosis (LAP), considered a non-cannonical autophagy pathway [8][9][10][11][12]. Professional phagocytes such as macrophages, monocytes and, dendritic cells as well as non-professional/specialized phagocytes such as mammary epithelial cells, retinal pigment epithelial (RPE) cells, and sertoli cells utilize LAP for optimal degradation of phagocytosed material including dead cells/cellular debris, and to recycle nutrients such as vitamin A derivatives [6,11,[13][14][15]. While LAP shares molecular machinery with CA, it is a distinct process; unlike CA, LAP is AMPK-mTORC1-ULK1 independent and unresponsive to nutrient status [8,11,16].…”