Abstract
p66SHC is a pro-oxidant member of the SHC family of protein adaptors that acts as a negative regulator of cell survival. In lymphocytes p66SHC exploits both its adaptor and its reactive oxygen species (ROS)-elevating function to antagonize mitogenic and survival signaling and promote apoptosis. As a result, p66SHC deficiency leads to the abnormal expansion of peripheral T and B cells and lupus-like autoimmunity. Additionally, a defect in p66SHC expression is a hallmark of B cell chronic lymphocytic leukemia, where it contributes to the accumulation of long-lived neoplastic cells. We have recently provided evidence that p66SHC exerts a further layer of control on B cell homeostasis by acting as a new mitochondrial LC3-II receptor to promote the autophagic demise of dysfunctional mitochondria. Here we discuss this finding in the context of the autophagic control of B cell homeostasis, development, and differentiation in health and disease.
Highlights
Reported as a longevity-related protein, the p66 kDa isoform of SHC1, a member of the SHC protein family, is a ubiquitously expressed protein that participates in a plethora of pathways through its ability to act both as an adapter that antagonizes tyrosine kinase-dependent mitogenic signaling and as a pro-oxidant molecule molecule that promotes stress-dependent apoptosis
As we will discuss we have identified a new survival-related function of p66Shc as regulator of B lymphocyte autophagy (Onnis et al, 2018), a process that regulates B cell fate, survival and differentiation, highlighting p66SHC as a pleiotropic master regulator of lymphocyte survival
We have recently reported that p66SHC affects B cell survival by antagonizing survival signaling by the BCR and promoting apoptosis, but unexpectedly through selective autophagy/mitophagy (Onnis et al, 2018)
Summary
Reported as a longevity-related protein, the p66 kDa isoform of SHC1, a member of the SHC protein family, is a ubiquitously expressed protein that participates in a plethora of pathways through its ability to act both as an adapter that antagonizes tyrosine kinase-dependent mitogenic signaling and as a pro-oxidant molecule molecule that promotes stress-dependent apoptosis. By acting as an early negative regulator of antigen receptor signaling, p66SHC impairs RAS/MAPK-dependent mitogenic signaling, and survival signaling mediated by the phosphatidylinositol kinase effector AKT (Capitani et al, 2010; Figure 1B) Consistent with this function, T and B cells from p66shc−/− mice show increased spontaneous and antigen-induced activation, proliferation and survival (Finetti et al, 2008). We have causally associated the disrupting effects of p66SHC on mitochondrial function to its ability to modulate the expression of several members of the BCL-2 family of apoptosis-regulating proteins (Pacini et al, 2004; Capitani et al, 2010; Figure 1B) This property can account for the Ca2+-elevating activity of p66SHC, which we found associated with a decrease in the levels of the plasma. As we will discuss we have identified a new survival-related function of p66Shc as regulator of B lymphocyte autophagy (Onnis et al, 2018), a process that regulates B cell fate, survival and differentiation, highlighting p66SHC as a pleiotropic master regulator of lymphocyte survival
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