Institute of Microbial Technology (सूक्ष्मजीव प्रौद्योगिकी संस्थान)
A Council of Scientific & Industrial Research (वैज्ञानिक औद्योगिक अनुसंधान परिषद)
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  About Targets  
  Various transcription factors and the cognate signaling molecules after sensing transmit the signal to the effectors which upregulate or downregulate the autophagic process. Yeast genetics has immensely widen our acquaintance with the molecular mechanisms of autophagy. About 30 autophagy related genes (ATGs) in yeast have been identified and homologues of these genes have been identified in mammals and they are largely conserved. The mammalian homolog of ATG6 is called Beclin1 (BECN1). This protein plays a crucial role in the regulation of autophagy. BECN1 forms a complex with the class III phosphatidylinositol 3-kinase (PIK3C3) known as Vps34 in yeast. In addition, UVRAG allies with the BECN1-PIK3C3 complex and augments autophagy. Two novel protein conjugation systems are indispensable for autophagosome formation: the ATG12-ATG5 and the GABARAPL2-phosphatidylethanolamine systems. ATG12-ATG5 conjugate assists the formation of autophagosomes. ATG8 (called LC3 in mammals) also aids autophagosome formation, perhaps by enhancing membrane fusion. Soluble LC3 is called LC3-I, and the lipidated, autophagosome-specific form is called LC3-II. The main core machinery for autophagy comprise of autophagy-related genes (ATGs) genes, such as ATG3, ATG5, ATG7, ATG12, other proteins such as unc-51 like autophagy activating kinase 1 (ULK1), BECN1, RAB7 and Phosphatidylinositol 3-kinase (PI3KC3). A number of other signaling molecules and transcription factors also modulate autophagy. Signaling molecules like Mechanistic target of rapamycin kinase (MTOR), Protein kinase AMP-activated (PRKA), PI3K, MAPKs and B-cell CLL/lymphoma 2 (BCL2) play an important role in maintaining dynamic cellular homeostasis. Transcription factor EB (TFEB), Forkhead box containing protein O subfamily (FOXO), E2 transcription factor (E2F), Activating transcription factor (ATF), Hypoxia inducible factor-1 (HIF1), and NFKB, are all transcription factors which regulate autophagy during various pathophysiological conditions. Furthermore, several nuclear receptors such as Vitamin D receptor (VDR), Peroxisome proliferator activated receptor gama (PPARG), Retinoic acid receptor (RAR), Nuclear receptor subfamily 3 group C member 1 (NR3C1) and Androgen receptor (AR), which comprise a subfamily of transcription factors also modulate autophagy through regulating the gene expression. These nuclear receptors in recent years have emerged as the most amenable drug targets due to varied nature of their agonists and antagonists which bind to them and activate and repress them under various physiological conditions.  
  Selective autophagy  
  Autophagy under basal conditions is considered as a non selective bulk degradation process which contributes to recycling of nutrients upon deprivation and starvation. However, in non starved cells autophagy plays a selective role as well and maintains intracellular homeostasis. It selectively degrades cargo materials such as damaged mitochondria (mitophagy) and endoplasmic reticulum (reticulophagy), misfolded and aggregated proteins (aggrephagy), invading pathogens (xenophagy) and surplus peroxisomes (pexophagy). Selective sequestration of cargo material in the phagophore is mediated by autophagy receptors for their selective turnover. An autophagy receptor plays a role in bridging the cargo material and autophagosomal membrane leading to its engulfment and autophagosome formation. In addition to autophagy receptors there are autophagy adaptor proteins which interact with Atg8 family of proteins. They do not participate in engulfment of the cargo instead they serve as an anchor point for cargo to autophagic machinery. Further they facilitate the initiation, conjugation, trafficking and fusion with the lysosome. In yeast five types of autophagy receptors have been discovered so far. These include Atg19 and Atg34 (Cvt pathway), Atg32 (mitophagy), Atg36 (pexophagy), and Atg30 (pexophagy). Most of these autophagy receptors have homologues in higher eukaryotes. Mammalian autophagy receptors and adaptors include SQSTM/p62, OPTN, NBR1, NDP52, NIX (NIP3-like protein X), FUNDC1 (FUN14 domain containing 1), ATG30, ATG36, ATG32, BNIP3, HDAC6, BAG1/BAG3, CHIP, PRKN, STBD1, DUBs and E3 ligases. These autophagy receptors and adaptors interact with the cargoes tagged with degradation signals and autophagososmal membranes and initiate phagophore generation which ultimately fuse with lysosomes for degradation. Unfortunately direct small molecule modulators for these protein targets are not available. Various indirect evidences for small molecule modulators for SQSTM/p62 protein are there and high throughput screening information regarding small molecule modulators for other protein targets is available on Pubchem and ChEMBL. Links to the indirect modulators and high throughput screening information is accessible on the homepage under search option.


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