Sterol Hormone 20E Regulates Autophagy via
Multiple Pathways in Insect
Wenmei Wu1, Yichen Dai1, Kang Li2 and Ling Tian1*
1Guangdong Provincial Key Laboratory of Agro-animal Genomics and Molecular Breeding/Guangdong Provincial Sericulture and Mulberry Engineering Research Center, South China Agricultural University, China
2Guangdong Provincial Key Laboratory of Insect Developmental Biology and Applied Technology, Institute of Insect Science and Technology, South China Normal University, China
Submission: July 01, 2019;; Published: July 11, 2019
*Corresponding author: Ling Tian, Professor, College of Animal Science, South China Agricultural University, Guangzhou, China
How to cite this article: Wenmei Wu, Yichen Dai, Kang Li, Ling Tian. Sterol Hormone 20E Regulates Autophagy via Multiple Pathways in Insect. Int J Environ Sci Nat Res. 2019; 20(3): 556037. DOI:10.19080/IJESNR.2019.20.556037
Keywords: 20E; Induction of autophagy; Multiple pathways; Insects
Sterol hormone 20-hydroxyecdysone (20E), specifically biosynthesized from cholesterol under the catalysis of a series of cytochrome P450 enzymes, is pivotal for insect molting and metamorphosis. Ecdysone, the precursor of 20E, is synthesized and secreted by a pair of prothoracic glands in holometabolous insects, and then is released into the hemolymph and converted to the active form 20E in peripheral tissues such as fat body, midgut and malpighian tubes during larval stage . In the adults of some insects, the presence of ecdysone in the ovary was recognized more than 40 years ago, and now it is well known that ovarian follicular cells produce ecdysone from scratch . However, in some Lepidoptera, male gonads also release in moderately large amounts of ecdysone in vitro  .
Via binding its receptor complex EcR-USP, 20E rapidly and highly induced the expression of primary-response genes including nuclear receptors or transcription factors such as E75, E93, Br-C, and E74, which are requisite for insect larval-pupal metarmorphosis [4-6]. 20E massively induced the expression of three different BmE75 isofoms in Bombyx, which consequentially coordinated feedback to 20E biosynthesis . E93 is encoded by a member of the helix-turn-helix (HTH) transcription factor family and is involved in the crosstalk of 20E signaling with juvenile hormone (JH) signaling via JH primary response gene Kr-h1 . Notably, 20E signaling predominantly mediates the occurrence of autophagy in larval tissue and organs during larval molting and larval-pupal metamorphosis .
In Drosophila, a peak of 20E at the end of the larval period triggers metamorphosis accompanying with elimination of the larval tissues, which are no longer necessary for adults, and to
recycle molecular materials for the formation of adult tissues . Moreover, 20E inhibits the PI3K/mTOR signaling to activate ATG1/ATG13 complex to initiate autophagosome formation in Drosophila fat body . 20E is necessary and sufficient to induce autophagy in larval tissue via upregulating the expression of several autophagy related (Atg) genes, implying ecdysone-induced autophagy as a crucial process in degradation of larval tissues . Furthermore, 20E signaling activates E93 to induce autophagy in Drosophila; in contrast, mutation of E93 blocks the destruction of the larval fat body via autophagy .
In Bombyx, 20E signaling is also found to upregulate autophagy through induction of most of all Atg gene expressions and inhibition of mTOR pathway. Moreover, the early-response transcription factors of 20E (i.e. Br-C, E74, E75, and E93) involved in its regulation on autophagy . Bombyx E75 was showed to be indispensable for autophagy induction during larval-pupal metamorphosis . Notably, the 20E primary response genes E93, which acts through GAGA-containing motifs, modulates 20E-EcR-USP to promote larval tissue remodeling and adult tissue formation during Bombyx larval-pupal metamorphosis . In addition, 20E induces starvation-like condition in Bombyx by reducing food consumption to trigger autophagy . Our previous work displayed that being cleaved into BmATG5 and BmATG6, BmATG5-tN and BmATG6-C mediated the switching between autophagy and apoptosis induced by their common stimuli 20E and starvation in Bombyx [11,12]. 20E is also reported to regulate autophagy beyond induction of Atg genes transcriptions and inhibition of mTOR signaling. In Helicoverpa armigera, 20E regulates the conjugation of ATG12–ATG5 in a concentration and time-dependent manner to promote insect midgut programmed cell death; moreover, 20E induces an increase
intracellular calcium levels, and thereby switches autophagic
cell survival to apoptotic cell death [13,14].
In addition, our previous studies found that 20E also
induced lysosome acidification ; nevertheless, the precise
mechanism is now well documented. Our recent works showed
that the developmental profiles of all Bombyx V-ATPases, which
were responsible for pumping protons across the plasma
membranes in numerous types of eukaryotic cells, were in
accordance with 20E titer in the hemolymph during larvalpupal
metamorphosis. 20E treatment induced V-ATPase gene
expression through the activation of transcription factor EB
and the subcomplex assembly of BmV-ATPases via promoting
the interaction between different subunits. In contrast, RNAi
of the 20E receptor gene BmUsp reduced both transcription
and translation of V-ATPases (in submission). Besides, we also
found that 20E dephosphorylated the histone deacetylase
BmRpd3, which mediates the deacetylation modification of ATG
proteins, and resulted in its nucleo-cytoplasmic translocation
and consequent promotion of autophagy occurrence (in
submission). In summary, 20E signaling upregulates autophagy
occurrence through multiple pathways including induction
of Atg and V-ATPases gene expression, inhibition of mTOR
pathway, and deacetylation modification of ATG proteins. For
the multifarious functions of the sterol hormone 20E signaling,
its deep physiological functions and the precise mechanism on
autophagy induction is worthy for further investigation.