Prof S. Murty Srinivasula
Professor (Biology)
  +91 (0)471 - 2778171


Delicate balance among diverse cellular pathways that control multiple biological processes is critical to maintain homeostasis in organisms. Knowledge, at the molecular level, of these fundamental physiological processes is essential to understand genetic basis for the development of numerous pathologies and to devise strategies for therapeutic intervention. Our research involves understanding of signaling mechanisms that control a few of these processes, namely autophagy, cell death and survival. Our team mainly focuses on identifying molecules and characterizing their function in regulating these pathways. Towards this end, we use several strategies, both in vitro and in vivo, and employ numerous biochemical, molecular and cell biological, immunological, and imaging techniques. Our research involves usage of cell lines originated from humans and rodents, primary immune cells isolated from mice, and in a few cases mice.

Signaling via surface receptors that recognize pathogen associated molecular patterns (PAMPs) such as toll-like receptors (TLRs) or cytokines that belong to tumor necrosis factor (TNF) family has been implicated in augmenting autophagy(Fig. 1).

Figure 1. Toll-like receptors (TLRs) sense pathogen-associated markers and initiate diverse immune responses including autophagy in host defense.

Autophagy is a membrane trafficking process by which endogenous or exogenous material is delivered to lysosomes, the primary catabolic compartments of eukaryotic cells. In this process double-membrane vesicles (referred to as autophagosomes), assembled de novo in a series of steps, sequester cytosol containing intracellular proteins, damaged organelles, and exogenous material like microbes and fuse with lysosomes to form autophagolysosomes where the cargo is eventually degraded(Fig. 2).

Figure 2. Autophagy is a catabolic process by which cells target cytoplasmic constituents to the lysosomes for degradation. Autophagy helps cells survive under starvation conditions by restoring nutrient and energy balance, and promote host defense by regulating innate and adaptive responses. Evidence has a implicated autophagy in cancer, obesity, aging and neurological disorders.

Autophagy was originally believed to be a catabolic process that helps cells survive under starvation conditions by restoring nutrient and energy balance. Subsequent findings however established a role for autophagy in various cellular processes involved in cell death, ageing, metabolism and host defense. Increasing evidence implicated autophagy with the pathogenesis of a wide variety of diseases, including, certain myopathies, neurodegenerative diseases, and chronic infections. Host defenses against bacterial, parasitic, and viral pathogens by autophagy range from directly targeting the pathogens for degradation in acidic lysosomal organelles to facilitate cytokine and interferon responses. Selective removal of invading microbes using the autophagic machinery, termed xenophagy, has been suggested to play a key role in this process by destruction of several kinds of bacteria, including Escherichia coli, Mycobacterium tuberculosis, as well as parasites such as Toxoplasma gondii. Autophagy also contributes to protection against infection by viruses such as vesicular stomatitis virus and Sindbis virus. Because in some contexts autophagy can lead to cell death, a conundrum presently exists concerning the role of autophagy in cancer. On the one hand, autophagy confers a growth advantage to tumor cells under poor nutrient conditions. On the other, defects in autophagy promote accumulation of damaged/dysfunctional organelles and proteins that can lead to DNA damage and the generation of tumorigenic clones. Although some core proteins involved in the assembly of autophagosomes have been identified, very little of the proximate signaling that lead to autophagosome formation, and the physiological consequences of their assembly in response to invasion by foreign organisms is known. Importantly, the immune-enhancing functions of autophagy in primary cells and in mouse models of microbial infection remain to be established. The primary focus of my research is to understand the role played by TLR-mediated autophagy (Fig. 3) in host defense and to elucidate the molecular pathways involved in the process.

Figure 3. Activation of TLR-4 signaling results in accumulation LC3-positive structures.

Additionally, our research involves understanding of cross talk between cell death regulators such as caspases, inhibitors of apoptosis proteins (IAPs) and cell survival mechanisms such as NF-kappaB signaling pathways.