A chimerical phagocytosis model reveals the recruitment by Sertoli cells of autophagy for the degradation of ingested illegitimate substrates

Abstract

Phagocytosis and autophagy are typically dedicated to degradation of substrates of extrinsic and intrinsic origins respectively. Although overlaps between phagocytosis and autophagy were reported, the use of autophagy for ingested substrate degradation by nonprofessional phagocytes has not been described. Blood-separated tissues use their tissue-specific nonprofessional phagocytes for homeostatic phagocytosis. In the testis, Sertoli cells phagocytose spermatid residual bodies produced during germ cell differentiation. In the retina, pigmented epithelium phagocytoses shed photoreceptor tips produced during photoreceptor renewal. Spermatid residual bodies and shed photoreceptor tips are phosphatidylserine-exposing substrates. Activation of the tyrosine kinase receptor MERTK, which is implicated in phagocytosis of phosphatidylserine-exposing substrates, is a common feature of Sertoli and retinal pigmented epithelial cell phagocytosis. The major aim of our study was to investigate to what extent phagocytosis by Sertoli cells may be tissue specific. We analyzed in Sertoli cell cultures that were exposed to either spermatid residual bodies (legitimate substrates) or retina photoreceptor outer segments (illegitimate substrates) the course of the main phagocytosis stages. We show that whereas substrate binding and ingestion stages occur similarly for legitimate or illegitimate substrates, the degradation of illegitimate but not of legitimate substrates triggers autophagy as evidenced by the formation of double-membrane wrapping, MAP1LC3A-II/LC3-II clustering, SQSTM1/p62 degradation, and by marked changes in ATG5, ATG9 and BECN1/Beclin 1 protein expression profiles. The recruitment by nonprofessional phagocytes of autophagy for the degradation of ingested cell-derived substrates is a novel feature that may be of major importance for fundamentals of both apoptotic substrate clearance and tissue homeostasis.

Autophagy is required for ectoplasmic specialization assembly in sertoli cells

“…54,55 They therefore could not present the exogenous constriction force, and so the precise function remains controversial. 13 Autophagy is active in Sertoli cells, [26][27][28][29] and early morphology studies found that the lysosomes of the seminiferous epithelium show cyclical variations. Chemes speculates that germ cell residual body disposal might be initiated by autophagy and completed by Sertoli cell phagocytosis.…”

“…20 Autophagy participates in cell growth, adaptation to stress conditions, anti-aging mechanisms, intracellular quality control, renovation during development and differentiation and the biogenesis of organelles such as cilia and acrosome. 21,[23][24][25] Autophagy is also active in Sertoli cells, [26][27][28][29] where it is involved in the clearance of SHBG/ABP that is selectively regulated by testosterone. 26 However, the role of autophagy in Sertoli cells is still largely unknown.…”

4-Nonylphenol induces autophagy and attenuates mTOR-p70S6K/4EBP1 signaling by modulating AMPK activation in Sertoli cells

“…There is increasing evidence that autophagy plays a regulatory role in spermatogenesis impairment targeting the injurious biochemical and molecular cascade (Wang et al 2014b;Yefimova et al 2013). …”

Contribution of Autophagy to the Physiological and Pathophysiological Functions in the Mammalian Testis

“…Nevertheless, autophagy is selectively involved in the degradation of those illegitimate substrates in Sertoli cells, and the inhibition of autophagy significantly retarded the degradation of illegitimate substrates [47].…”

“…In Sertoli cells, both autophagy and phagocytosis may undertake similar mission under certain circumstance, especially once a phagocytic vesicle has entered a cell. Numerous evidences had suggested that autophagy is associated with the process of phagocytosis and is atypically implicated in the degradation of external substrates entering via phagocytosis in Sertoli cells [47]. Generally, blood-separated tissues use their tissue specific nonprofessional phagocytes for homeostatic phagocytosis [48].…”