Nazma Malik
“We aim to understand how energy metabolism intersects with and shapes certain biological processes, particularly energy-intensive ones like the immune response, especially within the tumour microenvironment.”
AMP-activated protein kinase (AMPK), an ancient energy sensor, monitors and maintains cellular energy levels by inhibiting energy-consuming anabolic processes and promoting energy-generating catabolic pathways under conditions of energy stress.
As a central regulator of metabolism and energy balance, AMPK influences multiple aspects of mitochondrial homeostasis, including mitophagy, fission, and biogenesis. Our recent work has uncovered how AMPK regulates mitochondrial biogenesis through its substrate FNIP1, the MIT/TFE family of transcription factors and PGC1α, solving a long-standing mechanistic puzzle.
While AMPK’s role in metabolic conditions like diabetes and obesity is well known, its impact on other biological processes, such as immunity and aging, remains less well understood. Since all cells require energy to function, understanding AMPK’s influence on energy intensive processes, where energy dysregulation is likely to play a significant role, is crucial.
Our lab is focused on deciphering how AMPK and mitochondrial pathways affect innate and adaptive immunity, particularly within the tumour microenvironment. Although cancer immunotherapy, such as immune checkpoint blockade, has revolutionized cancer treatment, most patients do not respond. Evidence suggests that energy dysregulation may impact various aspects of the immune response.
Using a combination of CRISPR/Cas9 gene editing, proteomics, transcriptomics and biochemical techniques, we aim to explore how AMPK metabolism influences immune pathways in cancer. We will be investigating whether AMPK signalling pathways can be harnessed to enhance cancer immunotherapy and address aging-related conditions.
Selected Publications
Malik N, Ferriera B, Hollstein P, Curtis S D, Trefts E, Weiser-Novak S, Yu J, Gilson R, Hellbery K, Fang L, Sheridan A, Hah N, Shadel G, Manor U, Shaw R J. Induction of lysosomal and mitochondrial biogenesis by AMPK phosphorylation of FNIP1. Science. 2023 Apr 21; Vol. 380: no. 6642
Hung CM, Lombardo P, Malik N, Brun S N, Hellberg K, Van Nostrand J L, Garcia D, Baumgart J, Diffenderfer K, Asara J M, Shaw R J. AMPK/ ULK1-mediated phosphorylation of Parkin ACT domain mediates an early step in mitophagy. Science Advances. 2021 Apr 7; Vol. 7, no. 15
Malik N, Nirujogi R, Peltier J, Macartney T, Whightman M, Prescott A R, Gourlay R, Trost M, Alessi D, Karapetsas T. Phosphoproteomics reveals that the hVPS34 regulated SGK3 kinase specifically phosphorylates endosomal proteins including Syntaxin-7, Syntaxin-12, RFIP4 and WDR44. Biochem J. 2019 Oct 30; 475(1):117-135.
Malik N, Macartney T, Hornberger A, Anderson K, Prescott A, Alessi D. Mechanism of Activation of SGK3 by growth factors via the Class I and Class III pathways. Biochem J. 2018 Jan 2;475(1):117-135.
Malik N., Vollmer S., Nanda S.K., Lopez-Pelaez M., Prescott A., Gray N., Cohen P. Suppression of interferon β gene transcription by inhibitors of bromodomain and extra-terminal (BET) family members. Biochem J. 2015 468: 363–372.
Bago R, Malik N, Munson MJ, Prescott AR, Davies P, Sommer E, Shpiro N, Ward R, Cross D, Ganley IG, Alessi D Characterization of VPS34-IN1, a selective inhibitor of Vps34, reveals that the phosphatidylinositol 3-phosphate-binding SGK3 protein kinase is a downstream target of class III phosphoinositide 3-kinase. Biochem J. 2014 463: 413-427
