Mechanism of cGAS-STING Inactivation in Antitumor Immunity and Disease

2020 Emerging Leader Award

Philip Kranzusch, PhD, Dana-Farber Cancer Institute

Philip Kranzusch, PhD

Dr. Kranzusch is investigating how the signaling molecule cGAMP is controlled within cells, research that is critical for the rational design of next-generation anti-cancer immunotherapies. cGAMP carries immunity-stimulating signals between the enzyme cGAS and the receptor STING, which can spread rapidly from cell to cell to activate a widespread antitumor immune response. Researchers in the Kranzusch laboratory are studying the mechanism and downstream immune effects of cGAMP regulation, including identifying the key biological factors involved in cGAMP degradation. Dr. Kranzusch earned his PhD from Harvard University and completed postdoctoral studies at University of California, Berkeley. In 2016 he started as an Assistant Professor of Microbiology at Harvard Medical School and the Dana-Farber Cancer Institute. The Kranzusch Lab uses a biochemical and structural biology approach to understand the immune response to cancer.

published research

Eaglesham JB, McCarty KL, Kranzusch PJ. Structures of diverse poxin cGAMP nucleases reveal a widespread role for cGAS-STING evasion in host-pathogen conflict. Elife. 2020.

Govande AA, Duncan-Lowey B, Eaglesham JB, Whiteley AT, Kranzusch PJ. Molecular basis of CD-NTase nucleotide selection in CBASS anti-phage defense. Cell Rep. 2021.

Slavik KM, Morehouse BR, Ragucci AE, Zhou W, Ai X, Chen Y, Li L, Wei Z, Bähre H, König M, Seifert R, Lee ASY, Cai H, Imler JL, Kranzusch PJ. cGAS-like receptors sense RNA and control 3’2′-cGAMP signaling in Drosophila. Nature. 2021.

Tal N, Morehouse BR, Millman A, Stokar-Avihail A, Avraham C, Fedorenko T, Yirmiya E, Herbst E, Brandis A, Mehlman T, Oppenheimer-Shaanan Y, Keszei AFA, Shao S, Amitai G, Kranzusch PJ, Sorek R. Cyclic CMP and cyclic UMP mediate bacterial immunity against phages. Cell. 2021.

Duncan-Lowey B, McNamara-Bordewick NK, Tal N, Sorek R, Kranzusch PJ. Effector-mediated membrane disruption controls cell death in CBASS antiphage defense. Mol Cell. 2021.

Hobbs SJ, Wein T, Lu A, Morehouse BR, Schnabel J, Leavitt A, Yirmiya E, Sorek R, Kranzusch PJ. Phage anti-CBASS and anti-Pycsar nucleases subvert bacterial immunity. Nature. 2022.

Morehouse BR, Yip MCJ, Keszei AFA, McNamara-Bordewick NK, Shao S, Kranzusch PJ. Cryo-EM structure of an active bacterial TIR-STING filament complex. Nature. 2022.

Zhou W, Richmond-Buccola D, Wang Q, Kranzusch PJ. Structural basis of human TREX1 DNA degradation and autoimmune disease. Nat Commun. 2022.

Mosallanejad K, Kennedy SN, Bahleda KM, Slavik KM, Zhou W, Govande AA, Hancks DC, Kranzusch PJ, Kagan JC. Species-specific self-DNA detection mechanisms by mammalian cyclic GMP-AMP synthases. Sci Immunol. 2023.

Slavik KM, Kranzusch PJ. CBASS to cGAS-STING: The Origins and Mechanisms of Nucleotide Second Messenger Immune Signaling. Annu Rev Virol. 2023.

Li Y, Slavik KM, Toyoda HC, Morehouse BR, de Oliveira Mann CC, Elek A, Levy S, Wang Z, Mears KS, Liu J, Kashin D, Guo X, Mass T, Sebé-Pedrós A, Schwede F, Kranzusch PJ. cGLRs are a diverse family of pattern recognition receptors in innate immunity. Cell. 2023.

Cai H, Li L, Slavik KM, Huang J, Yin T, Ai X, Hédelin L, Haas G, Xiang Z, Yang Y, Li X, Chen Y, Wei Z, Deng H, Chen D, Jiao R, Martins N, Meignin C, Kranzusch PJ, Imler JL. The virus-induced cyclic dinucleotide 2’3′-c-di-GMP mediates STING-dependent antiviral immunity in Drosophila. Immunity. 2023.

Antine SP, Johnson AG, Mooney SE, Leavitt A, Mayer ML, Yirmiya E, Amitai G, Sorek R, Kranzusch PJ. Structural basis of Gabija anti-phage defence and viral immune evasion. Nature. 2023.

Johnson AG, Mayer ML, Schaefer SL, McNamara-Bordewick NK, Hummer G, Kranzusch PJ. Structure and assembly of a bacterial gasdermin pore. Nature. 2024.

Richmond-Buccola D, Hobbs SJ, Garcia JM, Toyoda H, Gao J, Shao S, Lee ASY, Kranzusch PJ. A large-scale type I CBASS antiphage screen identifies the phage prohead protease as a key determinant of immune activation and evasion. Cell Host Microbe. 2024.