Academia

Following medical school, Dixit completed a residency in the Department of Pathology at the Washington University School of Medicine. He decided to pursue pathology because he had been interested in the process of death since childhood and pathology offered more research options across medical disciplines.^[3]

Encouraged to train in research as part of the residency program, Dixit found a position in the lab of biochemistry professor William Frazier and became involved in a project on thrombospondin, a protein in the extracellular matrix.^[7] The project's success a few years later resulted in a number of publications. Congruent with his research, Dixit chose to specialize in hemostasis and thrombosis during his last year of clinical training.^[7]

In 1986 he joined the University of Michigan Medical School Department of Pathology as an assistant professor, eventually becoming a full professor.^[6] During his early years as an assistant professor, Dixit's research focused on thrombospondin. In 1994 his interests shifted and he began to reorient his research to cell death.^[3]

Genentech

In 1997, Dixit became the Director of Molecular Oncology at Genentech.^[8][6] In 2009 he led the Department of Physiological Chemistry.^[9] As of 2016 he held the position of Vice President of Discovery Research,^[2] and oversaw Genentech's postdoctoral program.^[3]

Early research on thrompospondin

While at the University of Michigan, he received funding from the National Institutes of Health to support research into thrombospondin, as his laboratory had shown this protein had a role in promoting cancer metastases.^[3]

Caspases and apoptosis

In 1991, an article in Scientific American inspired Dixit to study how tumor necrosis factors, which are responsible for the regulation of immune cells, trigger inflammation and cell death.^[13]

Dixit switched research tracks and began investigating cell death mechanisms. The research identified each component of the cell-death pathway and explained how they were all connected.

In 1996, he published the first evidence that death receptors engaged a mammalian deathase, a molecular scissors (protease) that cleaves proteins.^[14] His team's work on death receptor-induced apoptosis was notable, for prior to that time, cell surface receptors were thought to signal by functioning as ion channels or altering intracellular phosphorylation. Death receptors, however, signal by a different mechanism—activation of a death protease.^[15]

Collaborating with Guy Salvesen's group at the Burnham Institute, Dixit's group proposed the model of proximity-induced autoactivation in 1998 to explain how the first proteolytic signal is generated by caspase precursors recruited to death receptors.^[16]

RIP kinases, NF-κB signaling and necroptosis

At Genentech, Dixit formed a team with the goal of unraveling the complex interplay between cell death and inflammation at the molecular level.^[5] During his tenure, he has worked on the innate immune system, particularly its role in orchestrating an inflammatory response to fight pathogens and cancer.^[17]

In 1999, his team discovered RIPK2 and RIPK3, which later were shown to be key mediators of NF-κB signaling and necroptosis, respectively.^[18] Incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, and improper immune development.

Dixit's work contributed to the discovery of a core complex composed of three proteins that enabled antigen receptors to activate the canonical NF-κB pathway: CARD11, BCL10 and MALT1/paracaspase.^[19] Furthermore, he postulated a protease activity for MALT1, which plays a role in T cell activation and MALT lymphomas.^[20] His team described the family of metacaspase proteases in plants in a paper published in 2000.^[20]

In a series of papers between 2016 and 2020, Dixit and his colleagues at Genentech also worked out the complex molecular mechanisms that regulate activity of caspase-8, OTULIN, RIPK1, RIPK3 and other proteins that modulate inflammation, apoptosis and necroptosis signaling by death receptors and TLRs.^{[21][22][23][24][25]}

Inflammasomes and pyroptosis

By 2002, Dixit was among the first scientists to demonstrate that pro-inflammatory caspases are part of a molecular complex named inflammasomes that are integral to the proper functioning of the innate immune system.^[26] In particular, he defined regulatory components upstream of caspase-1 that proteolytically activate the pro-inflammatory cytokines interleukin-1beta and interleukin-18.^[3]

In 2004 and 2006, Dixit provided unequivocal genetic evidence by identifying the NOD-like receptors NLRP3 and NLRC4 as proximal components of inflammasomes responsible for caspase-1 activation.^[3][27] The research showed that inflammasomes distinguish between inflammatory triggers, such as differentiating between types of bacteria, through the use of different sensors. 

More specifically, the intracellular protein NLRC4 was identified as a sensor for Salmonella that triggered assembly of an inflammasome complex.^[27] NLRP3 and the inflammasome adaptor ASC, on the other hand, were found to be required for activation of the inflammasome by diverse pathogenic agents, including microbial toxins, and Gram-positive bacteria such as Staphylococcus aureus or Listeria monocytogenes.

In 2009, his group followed up on these findings with the discovery of the first small molecule inhibitors of the NLRP3 inflammasome.^[28] Derived analogs of this sulfonylurea class of compounds are currently in clinical development for inflammatory and neurodegenerative diseases.^[29]

Dixit's team discovered the non-canonical inflammasome pathway and its critical role in mediating lethal systemic inflammation in response to Gram-negative pathogens, detailed in three papers in 2011,^[30] 2013,^[31] and 2015.^[32] This illuminated a new pathway to sepsis, a syndrome responsible for millions of deaths worldwide. Hence, targeting this pathway for therapeutic benefit is a substantial effort in pharmaceutical companies.

The 2011 paper showed that mice lacking the gene that encodes caspase-1 also carry a mutation in a neighboring caspase gene, caspase-11 (caspase-4 in humans), which is responsible for many of the effects previously attributed to caspase-1, including sensitivity to sepsis.^[33]

The 2013 paper clarified the role of Toll-like receptor 4 and caspase-11 in inducing innate immune responses to Lipopolysaccharides (LPS), a cell wall component of Gram-negative bacteria. The research showed that recognition of intracellular LPS by innate immune cells leads to a form of necrotic, proinflammatory death, termed pyroptosis. They showed that these mechanisms did not depend on TLR4, but were rather mediated by caspase-11. This was significant, because for years it was assumed that TLR4 was solely responsible for cellular responses to LPS.^[34]

In the 2015 paper, they used mice subjected to random mutation to find mediators of caspase-11-dependent non-canonical inflammasome signaling. This led to the discovery that caspase-mediated cleavage of the protein GSDMD creates a pore forming, plasma membrane disrupting amino-terminal fragment that induces pyroptosis.^[35] The advances contributed to firmly establishing the sequence of events leading from inflammasome activation to pyroptosis, DAMP release, and lethal septic shock.^[36]

Using a similar research strategy, in 2021, they reported NINJ1 to be a mediator of plasma membrane rupture and DAMP release from pyroptotic cells.^[37]

Ubiquitin signaling (A20, LUBAC, OTULIN)

In 1990, Dixit's lab at the University of Michigan discovered tumor necrosis factor (TNF)-inducible genes in endothelial cells, including A20/TNFAIP3.^[38] In later years, A20/TNFAIP3 would also achieve prominence as a modulator of inflammation.^[39]

In 2004, Dixit's group at Genentech discovered “ubiquitin editing” as a damping mechanism  that attaches ubiquitin tags to TNF-receptor associated proteins to switch off pro-inflammatory signaling.^[3][40]

In 2018, in a similar vein, his group showed that the ubiquitin-cleaving enzyme, OTULIN, regulates cell death and inflammation by removing inhibitory linear ubiquitin chains from LUBAC, an enzyme that activates NF-κB.^[21]