GRIM-19: A Double-edged Sword that Regulates Anti-Tumor and Innate Immune Responses

Abstract

Gene associated with retinoid-interferon-β-induced mortality (GRIM)-19, was originally identified as a critical regulatory protein necessary for Interferon-β-Retinoic acid-induced cell death. Overexpression of GRIM-19 activates cell death and its suppression or inactivation promotes cell growth. GRIM-19 targets multiple proteins/pathways for exerting growth control and cell death. However, GRIM-19 is also required for normal cellular processes. In addition, viruses 'hijack' GRIM-19 for their survival. Intracellular bacterial infections and bacterial products have been reported to induce the expression of GRIM-19. In this review, we will discuss the current status of GRIM-19 in growth control and innate immune response.

Keywords: apoptosis; cytokines; transcriptional inhibition and immune response; tumor suppression.

Figure 1

Viral Inhibitors of GRIM-19. Viruses effectively block GRIM-19’s action either by preventing its release from mitochondria and/or its action by sequestering with viral gene products. Lines in Red indicate blockade of GRIM-19 action involving the indicated viral components. Lines in Green indicate transcriptional repression. Mechanism of transcriptional repression is not known.

Figure 2

Cellular roles of GRIM-19. GRIM-19 appears to have more functions than previously envisaged: 1) It targets growth-promoting proteins, STAT3 and Src, to achieve growth control; 2) It augments the activity of HtrA2 to cleave XIAP; 3) In conjunction with NOD2 it participates in innate immune responses. GRIM-19 can perform these functions only when it is present in more than one intra-cellular compartment. For example, nuclear and cytosolic GRIM-19 can effectively block STAT3 and Src, respectively. GRIM-19 overexpression effectively blocks cell motility by decreasing tubulin polymerization. Upon IFN/RA stimulation, the de-novo synthesized GRIM-19 participates in growth control in conjunction with other proteins. Requirement of GRIM-19 for complex-I assembly and stability vis-à-vis ATP generation, is one of its reported functions. Red colored-lines and arrows represent GRIM-19-dependent inhibitory and stimulatory pathways, respectively. Blue colored lines and arrows represent STAT3-dependent inhibitory and stimulatory pathways, respectively. Green arrows represent novel GRIM-19 inductive and functional pathways. P in green and pink colored circles indicate phosphorylations at Serine 727 and tyrosine 705 residues, respectively.

Figure 3

Function of GRIM-19 in steady-state. Coordinated synthesis cum assembly of mitochondrial complex-I has been well-characterized. In addition to the structural and functional proteins in complex-I, distantly-related proteins like GRIM-19 and AIF are required for proper complex-I formation. Homozygous deletion of grim19 resulted in embryonic lethality in mice which may be a result of decreased complex-I levels in the developing embryo. M-coded—mitochondrial DNA-encoded, N-coded—Nuclear DNA-encoded.