Glucose-regulated protein (GRP78) is an important cell surface receptor for viral invasion, cancers, and neurological disorders.

The 78 kDa glucose-regulated protein (GRP78) is an endoplasmic reticulum (ER)-resident molecular chaperone. GRP78 is a member of the 70 kDa heat shock family of proteins involved in correcting and clearing misfolded proteins in the ER. In response to cellular stress, GRP78 escapes from the ER and moves to the plasma membrane where it (a) functions as a receptor for many ligands, and (b) behaves as an autoantigen for autoantibodies that contribute to human disease and cancer. Cell surface GRP78 (csGRP78) associates with the major histocompatibility complex class I (MHC-I), and is the port of entry for several viruses, including the predictive binding of the novel SARS-CoV-2. Furthermore, csGRP78 is found in association with partners as diverse as the teratocarcinoma-derived growth factor 1 (Cripto), the melanocortin-4 receptor (MC4R) and the DnaJ-like protein MTJ-1. CsGRP78 also serves as a receptor for a large variety of ligands including activated α2 -macroglobulin (α2 M*), plasminogen kringle 5 (K5), microplasminogen, the voltage-dependent anion channel (VDAC), tissue factor (TF), and the prostate apoptosis response-4 protein (Par-4). In this review, we discuss the mechanisms involved in the translocation of GRP78 from the ER to the cell surface, and the role of secreted GRP78 and its autoantibodies in cancer and neurological disorders.

Astrocytes, an active player in Aicardi-Goutières syndrome.

Aicardi-Goutières syndrome (AGS) is an early-onset, autoimmune and genetically heterogeneous disorder with severe neurologic injury. Molecular studies have established that autosomal recessive mutations in one of the following genes are causative: TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1 and IFIH1/MDA5. The phenotypic presentation and pathophysiology of AGS is associated with over-production of the cytokine Interferon-alpha (IFN-α) and its downstream signaling, characterized as type I interferonopathy. Astrocytes are one of the major source of IFN in the central nervous system (CNS) and it is proposed that they could be key players in AGS pathology. Astrocytes are the most ubiquitous glial cell in the CNS and perform a number of crucial and complex functions ranging from formation of blood-brain barrier, maintaining ionic homeostasis, metabolic support to synapse formation and elimination in healthy CNS. Involvement of astrocytic dysfunction in neurological diseases-Alexander's disease, Epilepsy, Alzheimer's and amyotrophic lateral sclerosis (ALS)-has been well-established. It is now known that compromised astrocytic function can contribute to CNS abnormalities and severe neurodegeneration, nevertheless, its contribution in AGS is unclear. The current review discusses known molecular and cellular pathways for AGS mutations and how it stimulates IFN-α signaling. We shed light on how astrocytes might be key players in the phenotypic presentations of AGS and emphasize the cell-autonomous and non-cell-autonomous role of astrocytes. Understanding the contribution of astrocytes will help reveal mechanisms underlying interferonopathy and develop targeted astrocyte specific therapeutic treatments in AGS.

Tolerogenic dendritic cells in the control of autoimmune neuroinflammation: an emerging role of protein-glycan interactions.

During the past decade, a great deal of information has contributed to our understanding of the immunosuppressive pathways that operate during the resolution of autoimmune pathology, including central nervous system (CNS) inflammation. Activation of these pathways is accomplished through the integration of an intricate network of inhibitory signals and immune suppressive cells, including regulatory T cells, myeloid-derived suppressor cells, 'alternatively activated' macrophages and tolerogenic dendritic cells (DCs). During the course of inflammatory diseases, immature or mature DCs may be licensed by different stimuli (e.g. cytokines, neuropeptides and growth factors) to become tolerogenic and suppress pathogenic T cell responses, thus emphasizing the outstanding plasticity of these cells. Recent findings have shed light to an immunoregulatory circuit by which galectin-1, an endogenous glycan-binding protein, favors the differentiation of regulatory DCs which promote T cell tolerance and contribute to resolution of autoimmune pathology through mechanisms involving IL-27 and IL-10. Together with the ability of galectin-1-glycan interactions to selectively blunt T helper (Th)1 and Th17 responses, this effect provides a rational explanation for the broad immunosuppressive effects of this glycan-binding protein in several experimental models of chronic inflammation and cancer. In this mini review, we will summarize the regulatory signals leading to the differentiation of tolerogenic DCs and their participation in CNS inflammation. In addition, we will underscore recent findings on the emerging role of galectin-glycan interactions in the establishment of immunosuppressive networks during the resolution of chronic inflammation.