One of the major questions that have driven my research interest throughout my scientific career is to understand the triggers of cell death and survival. To pursue some of the intriguing questions in biology our laboratory at the Institute of Health Sciences are currently working on the following projects:
Role of the PARP1/Sirtuin/Sarm1 axis in the regulation of mitochondrial homeostasis in aging and neurodegeneration
Mitochondria which are determinants of both ‘cell survival’ through the synthesis of ATP as well as ‘cell death’ by mediating apoptosis is the central theme to our ongoing projects. We are currently trying to understand the balance between cell death and survival mechanisms in the context of cellular metabolism with particular emphasis on the NAD+ pathway. The molecule of interest is Sarm1 (sterile alpha and TIR containing protein 1) which is a central regulator of programmed axonal degeneration. We have recently shown that early loss of NAD+ via PARP1 hyperactivation following mitochondrial complex I inhibition leads to defective mitophagy and Sarm1 induction. We are trying to connect how the NAD+ consuming enzymes like PARP1, Sirtuins as well as the pro-neurodegenerative molecule Sarm1 plays a role in neuronal cell death under mitochondrial complex I inhibition or in aging using both neuronal cell lines as well the model organism Drosophila melanogaster.
Host-Pathogen interaction
We are currently pursuing two questions to understand how the host innate immune response plays a determining role in the disease outcome:
i. Understanding the role of mitochondrial innate immune regulation during neurotropic virus infection
The first line of defense against a viral infection is to mount a productive Type-I interferon response that limits viral replication within host cells. Innate immune recognition of RNA viruses involves interactions at the mitochondria resulting in tradeoffs between efficiency vs fidelity of responses. While signaling via the MAVS signalosome is essential to limit viral replication it must also be stringently controlled to prevent hyperstimulation of immune responses. How this can be achieved? One negative regulator of MAVS is the pro-neurodegenerative molecule Sarm1, a member of the TLR adaptor family of proteins. Whether this is a strategy of the host to prevent axonal spread of viruses within the CNS or a subversion strategy adopted by the viruses to dampen MAVS-mediated interferon responses is an intriguing question that is the focus of our research using the neurotropic Chandipura virus (CHPV) as the model system.
ii. Role of the cGAS-STING pathway in cervical cancer
Cervical cancer which is the 4th most common cancer of women worldwide is caused by the persistence of high-risk HPV16 (~50%) or HPV18 (~15%) infection and HPV DNA is detectable in 90% of affected tissue. In recent years a host innate defense mechanism against invading DNA viruses have emerged that involve recognition of the cytosolic DNA by the receptor cGAS resulting in the production of the second messenger cGAMP which stimulates the receptor STING for the production of Type I interferons. Many viruses have evolved strategies of immune evasion by the cGas- STING pathways either via the masking of DNA ligands, post translational modification of STING or degradation of cGAMP. We are trying to elucidate the regulation of the cGAS-STING pathway in HPV-induced cervical cancer and gain a preliminary insight into the STING variants in Indian cervical cancer patients.
Postdoctoral training I (2006-2010)
For my first postdoctoral training with Dr. Mark Alexandrow at Moffitt Cancer Center, USA, we identified an effect of Transforming Growth Factor b1 (TGF-β1), a growth suppressive factor, on the assembly and function of the pre-replication complex (pre-RC) proteins (Cdc6, Cdt1 and Mcm2-7) which play a pivotal role during the G1/S transition of the cell cycle. We showed that TGFβ signals affect pre-RC dynamics depending on the cell cycle stage in G1. TGF-β treatment in early G1, prior to pre-RC assembly caused suppression of the oncoprotein cMyc and inhibition of CycE-Cdk2 complexes. In contrast, Retinoblastoma protein (Rb) controls TGF-β1 arrest in late G1 via direct targeting of the MCM helicase, specifically through Mcm7. This study demonstrated that Rb-E2F complexes are not the sole determinant of the S-phase entry in mammalian cell cycle and propose a novel tumor suppressor role for Rb (Mukherjee et al, PLoS One, 2009; Mukherjee et al, Molecular and Cellular Biology, 2010).
Post Doctoral training II (2010-2012)
In my second postdoctoral training with Dr. Karin Peterson at Rocky Mountain Laboratories, NIH, USA, I continued my pursuit in understanding the effects of infection induced immune response in cell death and apoptosis. In order to understand the mechanisms of neurodegeneration during CNS infection, we used a model of La Crosses virus, a tri-segmented negative sense RNA encephalitis virus. We identified a novel role of SARM1 (sterile alpha and TIR-1 containing protein 1, a negative regulator of TLR signaling) in inducing neuronal death during virus infection. Furthermore, we identified an interaction of SARM1 with MAVS, an anti-viral signaling molecule at the mitochondria and demonstrated the delicate balance of a good signaling molecule like MAVS going awry during neurodegeneration inducing neuronal apoptosis. This study provided a novel mechanism for virus-induced neuronal death and revealed new targets for the development of therapeutics to treat encephalitic viral infections (Mukherjee et al, Immunity, 2013).
Ph.D training (2000-2006)
During my Ph.D work under the guidance of Prof. A.C. Ghose at Bose Institute, Kolkata, I applied cell biology and immunology based approaches to study the mechanisms of immunosuppression associated with visceral leishmaniasis (VL). We successfully established an intracardial model of VL infection in mice that followed the progressive nature of Leishmania infection as often encountered in human infection (Mukherjee et al, Immunology Letters, 2003). Our study also showed the significant implication of Leishmania infection on the peripheral organs like lymph nodes and suggested that cells that are not infected per se also showed impaired proliferative response and induction of apoptosis during L. donovani infection in vivo. The cellular anergy in VL could be attributed to dephosphorylation of key molecules in the lymphocyte signaling pathway leading to their inactivation and subsequent apoptosis (Mukherjee et al, Apoptosis, 2006).
Administrative
Coordinator, Institute of Health Sciences, Presidency University (2022-present)
Coordinator, School of Biotechnology, Presidency University (2019-2022)
Member Secretary, insitutional Biosafety Committee (IBSC), Presidency University (2014-present)
Member, Gender Sensitization and Prevention of Sexual Harassment (GSPSHC) (2019-present)
Research
My research interest lies in understanding the interactions between cellular signaling components and their role in disease pathogenesis. We are looking at the role of NAD+ metabolism in cell death and survival using two opposing models: the model for neurodegeneration where we need to preseve the health of the cell and a cancer model where we need to prevent the uncontrolled cellular proliferation. To connect these two systems we are trying to elucidate the role of mirochondria as central regulators that ultimately determine cellular fate and how the availability/loss of NAD+ as driven by different enxymes like PARP1, Sirtuins or Sarm1 affects mitochondrial health and metabolism. We are also looking at the details of the regulation of the autophagy-lysosomal pathway as disease drivers and how deregulation of this pathway by a defective mitochondrial signaling or loss of NAD+ may be used in targeted therapy in both neurodegenerative diseases like Parkinson's disease or cancers like cervical cancer.
1. Sarkar A, Sur M, Dey P and Mukherjee P* (2022). Early loss of endogenous NAD+ following rotenone treatment leads to mitochondrial dysfunction and Sarm1 induction that is ameliorated by PARP inhibition. The FEBS Journal
2. Sarkar A, Kumari N and Mukherjee P*. (2021). The curious case of SARM1: Dr Jeckyll and Mr. Hyde in cell death and Immunity? The FEBS Journal.
3. Das S, Majumder T, Sarkar A, Mukherjee P, Basu S. (2020) Flavonoids as BACE1 inhibitors: QSAR modelling, screening and in vitro evaluation. Int J Biol Macromol. 165:1323
4. Dutta S, Das N, Mukherjee P*. (2020) Picking up a Fight: Fine Tuning Mitochondrial Innate Immune Defenses Against RNA Viruses. Front Microbiol. 11:1990
5. Sur M, Dey P, Sarkar A, Bar S, Banerjee D, Bhat S and Mukherjee P*. (2018). Sarm1 induction and accompanying inflammatory response mediates age-dependent susceptibility to rotenone-induced neurotoxicity. Cell Death Discovery. 4:114. *corresponding author
6. Mukherjee P, Winkler C, Taylor KG, Woods TA, Nair V, Khan BA, Peterson KE. (2015). SARM1, not MyD88, mediates TLR7/TLR9-induced apoptosis in neurons. J. Immunol. 195 (10):4913
7. Madeddu S, Woods TA, Mukherjee P, Sturdevant D, Butchi NB, Peterson KE. (2015). Identification of Glial Activation Markers by Comparison of Transcriptome Changes between Astrocytes and Microglia following Innate Immune Stimulation. PLoS One, e0127336
8. Mukherjee P, Tyson Woods, Roger Moore and Peterson KE. (2013). Activation of the Innate Signaling Molecule MAVS by Bunyavirus Infection Upregulates the Adaptor Protein SARM1, Leading to Neuronal Death. Immunity, 38 (4):705
9. Baker DG, Woods TA, Butchi NB, Morgan TM, Taylor RT, Sunyakumthorn P, Mukherjee P, Lubick KJ, Best SM, Peterson KE. (2013) Toll-like receptor 7 suppresses virus replication in neurons but does not affect viral pathogenesis in a mouse model of Langat virus infection. J Gen Virol. Feb; 94(Pt 2)
10. Mukherjee P, Butchi N.B., and Peterson K.E. (2012). Pattern Recognition Receptor activation of intrinsic brain cells and influence on viral neurovirulence. In Neuroinflammation:Pathogenesis, Mechanisms and Management. NOVA publishing.
11. Rajdeep Banerjee, Sudeep Kumar, Abhik Sen, Ananda Mookerjee, Mukherjee P, Syamal Roy, Subrata Pal and Pradeep Das (2011). TGF-β-regulated tyrosine phosphatases induce lymphocyte apoptosis in Leishmania donovani-infected hamsters. Immunology and Cell Biology. 89:573
12. Mukherjee P, Winter SL, Alexandrow MG (2010). Cell Cycle Arrest by TGFb1 near G1/S is mediated by acute abrogation of preRC activation involving an Rb-MCM interaction. Mol. Cell. Biol. 30(3):845
13. Mukherjee P, Majee SB, Ghosh S, Hazra B. (2009). Apoptosis-like death in Leishmania donovani promastigotes induced by diospyrin and its ethanolamine derivative. Int. J Antimicrob Agents. 34:596
14. Mukherjee P, Cao TV, Winter SL, Alexandrow MG (2009). Mammalian MCM loading in late-G1 coincides with Rb hyperphosphorylation and the transition to post-transcriptional control of progression into S-phase. PLoS One. 4:e5462
15. Mukherjee P, Sen PC, Ghose AC. (2006). Lymph Node Cells from BALB/c Mice with Chronic Visceral Leishmaniasis Exhibiting Cellular Anergy and Apoptosis on Stimulation with PMA Plus Ionomycin: Involvement of Ser/Thr phosphatase. Apoptosis.11:2013
16. Mukherjee P, Ghosh AK, Ghose AC. (2003). Infection pattern and immune response in the spleen and liver of BALB/c mice intracardially infected with L. donovani amastigotes. Immunol. Lett. 86 (2): 131-8
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