The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration

Abstract

Phosphatidylinositol-specific phospholipase Cγ2 (PLCγ2) is a critical signaling molecule activated downstream from a variety of cell surface receptors that contain an intracellular immunoreceptor tyrosine-based activation motif. These receptors recruit kinases such as Syk, BTK, and BLNK to phosphorylate and activate PLCγ2, which then generates 1D-myo-inositol 1,4,5-trisphosphate and diacylglycerol. These well-known second messengers are required for diverse membrane functionality including cellular proliferation, endocytosis, and calcium flux. As a result, PLCγ2 dysfunction is associated with a variety of diseases including cancer, neurodegeneration, and immune disorders. The diverse pathologies associated with PLCγ2 are exemplified by distinct genetic variants. Inherited mutations at this locus cause PLCγ2-associated antibody deficiency and immune dysregulation, in some cases with autoinflammation. Acquired mutations at this locus, which often arise as a result of BTK inhibition to treat chronic lymphocytic leukemia, result in constitutive downstream signaling and lymphocyte proliferation. Finally, a third group of PLCγ2 variants actually has a protective effect in a variety of neurodegenerative disorders, presumably by increased uptake and degradation of deleterious neurological aggregates. Therefore, manipulating PLCγ2 activity either up or down could have therapeutic benefit; however, we require a better understanding of the signaling pathways propagated by these variants before such clinical utility can be realized. Here, we review the signaling roles of PLCγ2 in hematopoietic cells to help understand the effect of mutations driving immune disorders and cancer and extrapolate from this to roles which may relate to protection against neurodegeneration.

Keywords: cancer; immunodeficiency; inflammation; neurodegeneration; phospholipase C.

Figure 1

Activity, structural domains, and known mutations of PLCγ2. A, PLCγ2 belongs to a group of intracellular enzymes that cleave the membrane phospholipid phosphatidylinositol-4,5-bisphosphate (PIP₂) to diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP₃), resulting in increased calcium signaling. B, PLAID-causing genomic deletions (Δ19 and Δ20–22) and APLAID-associated somatic mutations are located within the regulatory domain (S707Y, L848P, A708P) or in the C2 domain (M1141L) of PLCγ2. Acquired mutations as a result of BTK inhibition (S707Y, L845F) and the protective P522R variant in Alzheimer’s disease are found in the regulatory domain of PLCγ2. APLAID, PLCγ2-associated antibody deficiency and immune dysregulation with autoinflammation; C, carboxyl terminus; N, amino terminus; PLAID, PLCγ2-associated antibody deficiency and immune dysregulation; PLCγ2, phosphatidylinositol-specific phospholipase Cγ2.

Figure 2

Organs and tissues influenced by PLCγ2 in health and disease. An overview of the involvement of PLCγ2 at various anatomical sites in both normal physiology (left) and disease settings (right) in humans. PLCγ2, phosphatidylinositol-specific phospholipase Cγ2.

Figure 3

Opposing cellular effects of PLCγ2 mutations in APLAID. In APLAID, PLCγ2 mutations result in (A) stronger BCR signaling including Syk, Btk, and BLNK and elevated calcium responses and therefore negatively impact B cell development and (B) increased production of granulocytes and macrophages, which possibly depends on an increased GM-CSF receptor signaling. APLAID, PLCγ2-associated antibody deficiency and immune dysregulation with autoinflammation; PLCγ2, phosphatidylinositol-specific phospholipase Cγ2.

Figure 4

The PLCγ2 variant P522R is protective against neurodegeneration. In the brain, the γ2 isoform is predominantly expressed by microglia (right). When triggered by TREM2, the PLCγ2 variant P522R supports lipid metabolism, phagocytosis, and survival (left), thus protecting against Alzheimer’s disease (AD), Lewy body dementia, and frontotemporal dementia (FTD). PLAID, PLCγ2-associated antibody deficiency and immune dysregulation.