Dendritic cells (DC) are innate, antigen-presenting cells with the ability to prime and activate naïve T-cells (25–27). In this capacity, DC provide a link between the innate and adaptive arms of the vertebrate immune response. Immature DC reside in peripheral tissues where they surveil the environment for immunologic danger signals, specifically pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Upon encountering such signals, DC undergo maturation - a process characterized by the upregulation of major histocompatibility complex (MHC) antigen presentation molecules, co-stimulatory molecules that include CD40, CD80, CD83, CD86, and others, cytokine secretion (28, 29), and chemokine receptor expression (30). Mature DC then migrate to the peripheral lymphoid organs and present their most-recently sampled antigens to T-cells (30).

In DC, the mammalian mARS complex has been reported to take on unique features and roles pertinent to DC maturation and polarization. We have previously demonstrated that the composition of amino acyl tRNA synthetases within the complex may change depending upon the amino acid sequence composition of antigenic peptides presented by DC (31). If MHC class I and class II antigenic peptides share a stretch of identical amino acid homology, amino acyl tRNA synthetases of the corresponding, cognate amino acids join the complex, including those that are not canonically associated with mARS complexes. This peptide homology-mediated change in mARS complex composition is accompanied by the polarization of DC towards a T helper type 1 (T_H1) phenotype characterized by increased production of IL-12 and dissociation of AIMp1 from the mARS complex (31). Multiple studies have highlighted the T_H1-polarizing effects of AIMp1 on DC. We have elaborated on the critical role of AIMp1 in T_H1 immunity through characterization of AIMp1^-/- mice (32–34). Bone marrow-derived DC (BMDC) differentiated from AIMp1^-/- mice show significantly reduced proinflammatory cytokine expression including IL-12, IL-6, and IL-1β compared to WT BMDC following treatment with lipopolysaccharides (LPS). Moreover, T-cells co-cultured with AIMP^-/- DCs exhibited low levels of IFN-γ production. The loss of AIMp1 also impaired expression of CD86 and CD40 co-stimulatory molecules and p38 MAPK signaling in mature DC, resulting in a reduced ability of these cells to prime T-cells for anti-tumor and anti-viral responses (32). Moreso, analysis of data from GEO and TGCA databases demonstrated that elevated AIMp1 expression positively correlated with an increase in activated tumor-infiltrating DC and a T_H1 T-cell signature, and expression levels of AIMp1 were much better correlated with increased survival in melanoma, ovarian cancer, and breast cancer than were levels of IL-12 or IFN-γ expression, the mild correlations of which were insignificant (32).

DC maturation is a critical step that precedes its ability to activate T-cells. Following recognition of danger signals by pattern recognition receptors (PRRs), signaling cascades drive transcriptional and proteomic changes within DC. This reorganized transcriptome and proteome constitute DC polarization, the phenotype of which subsequently influences the identity and character of the downstream T_H response. Of the many signaling pathways involved, p38MAPK, mTORC1, NFkB and AP-1 are the most widely studied (35–40) and several subunits of the mARS complex regulate these pathways. For example, LysRs induces maturation and activation of DC through the MAPK and NFκB pathway (41). Kim reported that treatment of DC with lysRS leads to phosphorylation of a series of MAPK effectors including JNK, p38, and ERK as well as degradation of IκB, an inhibitory protein that prevents NFκB translocation into the nucleus. Consequently, LysRS treatment induces NFκB nuclear translocation where NFκB regulates genes important for DC polarization (41). Moreover, sequential inhibition of p38MAPK and NFκB demonstrated that inhibitors of MAPK effectors restored Iκα and Iκβ, suggesting the involvement of MAPK as an upstream regulator of NFκB in the LysRS-mediated maturation and activation of DC (41). In another study, AIMp1 treatment enhanced NFκB binding to the TLR2 promoter and modulated gene expression in DC (42), highlighting the role of NFκB in regulating transcriptional changes induced by mARS complex subunits. There exists additional evidence suggesting regulation of p38/MAPK by AIMp1. Inhibition of p38/MAPK suppressed the ability of DCs to produce IL-12 and consequently the ability to induce differentiation of IFN-γ-producing T-cells. Additionally, AIMp1 dissociation from the mARS complex influences the function of PP2A, a phosphatase that negatively regulates p38/MAPK activity. This observation was further validated in AIMp1^-/- mice in which both p38/MAPK and the BMDC T_H1 polarizing gene signature were substantially inhibited (32).

Upon maturation, DC adopt a transcriptional program characterized by increased expression of MHC antigen presentation complexes, co-stimulatory molecules (CD40, CD80, and CD86) and pro-inflammatory cytokines including IL-12, TNF, and IL-1β. Several studies have shown that various subunits of the mARS complex including AIMp1 and LysRS can upregulate this transcriptional signature in DC (32, 41, 43). Similarly, other aaRS including ThreRS (44), TrpRS (45), and TyrRS (46), not canonically known to associate with the mARS complex, have also been shown to regulate this transcriptional signature. Lastly, LysRS through its regulation of AP₄A synthesis has been shown to increase motility and antigen presentation functions of dendritic cells. As expected, BMDC from Nudt2^fl/fl /CD11c-cre mice in which AP₄A synthesis is enhanced due to the absence of Ap4A hydrolase prime a significantly stronger CD8⁺ T-cell responses highlighting the role of LysRS in regulating not only motility and antigen presentation, but functional activation of T cells as well (47). The roles of other subunits of the mARS complex in regard to DC function however remain elusive and therefore future studies will be critical to advance our understanding of this area.

Macrophages are tissue-resident antigen-presenting cells that play critical roles in maintaining tissue homeostasis. They mediate elimination of pathogen and damaged cells while coordinating tissue repair and remodeling. Depending on tissue microenvironment, macrophages can be polarized toward M1 or M2 subtypes, each subset having a unique role (48). M1 macrophages, also known as classically activated macrophages are characterized by the production of TNF, IL-1, IL-6, IL-12, and IL-23 following stimulation by IFNγ, GM-CSF, and LPS (48, 49). The polarization of macrophages toward the M1 phenotype is regulated by several signaling pathways including NFκB, AP-1, interferon-regulatory factor (IRF)-5, and signal transducer and activator of transcription 1 (STAT1) (50–53). These macrophages are critical for anti-viral, anti-bacterial, and anti-tumor immune responses due to their ability to produce microbiocidal and tumoricidal substances including nitric oxide (NO) and reactive oxygen species (ROS). Conversely, M2 macrophages, also known as alternatively activated macrophages, upregulate the anti-inflammatory cytokine IL-10 and downregulate the proinflammatory cytokine IL-12. M2 macrophages also exhibit increased production of arginase-1 (Arg-1), an enzyme known to deplete L-arginine thereby impairing T-cell activation and function. Macrophages become polarized toward the M2 phenotype through a controlled signaling cascade involving STAT6, IRF-4, peroxisome proliferator-activated receptor (PPAR)-γ, and cAMP-responsive element-binding protein (CREB) (24, 54). M2 macrophages are implicated in the propagation of chronic inflammation, tumorigenesis, and metastasis (48, 55), and therefore maintenance of tissue homeostasis generally requires tight regulation of M1/M2 polarization.

Several subunits of the mARS complex have been implicated in the regulation of macrophage polarization. For instance, LysRS expressed by colon cancer cells induces the polarization of tumor-associated macrophages (TAMs) toward the M2 phenotype which in turn activates cancer cells and cancer-associated fibroblasts (CAFs) to regulate metastasis (56). LysRS-positive cancer cells secrete cytokines including GAS6, IL-8, and ANG which can reprogram M1 macrophages toward an M2 phenotype, thereby facilitating subsequent tumor infiltration (56). This study however did not report on the role of endogenous LysRS in macrophage polarization. Another study reported that LysRS induces the production of proinflammatory cytokines from macrophage-like THP-1 cells following activation by Shiga toxin (Stx) (57). Shiga toxins are virulence factors produced by Shigella dysenteriae and human pathogenic Shiga toxin-producing Escherichia coli (STEC). The toxin is comprised of two subunits, subunit A which has enzymatic activity, and subunit B which is critical for receptor-mediated entry. The enzymatic Stx subunit A has been shown to induce LysRS dissociation from the mARS complex and its subsequent secretion from differentiated THP-1 macrophage-like cells. Indeed, co-treatment of THP-1 cells with Stx plus purified LysRS enhanced the production of proinflammatory cytokines much more than each alone; suggesting that Stx may mediate its proinflammatory effects by inducing release of LysRS which may then act in an autocrine fashion to propagate inflammation (57). Interestingly, GluProRS has been shown to inhibit translation of proinflammatory cytokines in macrophages following IFNγ treatment (58). IFN-γ induces a series of signaling events that lead to the activation of cyclin-dependent kinase (Cdk-5) and its regulatory protein Cdk5R1(p35) which phosphorylate GluProsRS at Ser886 and induce downstream phosphorylation at Ser999. This signaling event leads to the release of GluProRS from the mARS complex, and its association with the GAIT complex. During GAIT assembly, NSAP1 interacts with GluProRS to form the pre-GAIT complex after which other partners join to form the active GAIT complex. GluProRS in the GAIT complex then directly binds the 3’UTR GAIT element on target mRNAs while P-L13a interacts with elF4G of the translation initiation complex to block assembly of small ribosomal subunits and consequently the initiation of translation (22, 58). Through these mechanisms, the mARS complex manipulates translation of specific genes that regulate macrophage phenotype.

Several signaling pathways are involved in the regulation of macrophage phenotype, and mARS complex subunits have been reported to play key roles in this process. LysRS activates p38MAPK to induce TNF expression and cell migration, and LysRS treatment of macrophages upregulates production of matrix metalloproteinase 9 (MMP-9) to aid in tissue invasion (59). Additionally, Glu-ProRS regulates antiviral immunity in macrophage-like U937 and RAW264.7 cells (60). Upon viral infection, GluProRS undergoes infection-specific phosphorylation at Ser990 which induces its dissociation from the mARS complex and participation in functions distinct from its known roles in the GAIT complex. GluProRS is a positive regulator of the RIG-I and MDA5-mediated type I interferon pathway and acts downstream of mitochondrial antiviral signaling protein (MAVS) and upstream of TRAF3. GluProRS interacts with PCB2, a negative regulator of MAVS which is known to trigger he ubiquitination and degradation of MAVS after viral infection. MAVS is a key protein in a signaling cascade important for anti-viral immune responses. The GluProRS-PCBP2 interaction blocks PCBP2-mediated ubiquitination of MAVS which then propagates the antiviral signaling cascade that suppresses viral replication (60). Moreover, GluProRS knockdown reduced antiviral responses demonstrated by lowering IFN-γ and IL-6 production following viral infection or treatment with synthetic double-stranded RNA poly(I:C) (60). As expected, stable overexpression of GluProRS in these cells rescued the antiviral phenotype and upregulated innate antiviral immunity against RNA viruses. GluProRS heterozygotes exhibited higher levels of influenza viremia, produced lower levels of the inflammatory cytokines IFN-β and IL-6, and delayed viral clearance in comparison to GluProRS wildtype animals (60). The ability of GluProRS to play distinct roles depending on cellular cues demonstrates the role of the mARS complex and indeed its subunits in sensing and maintaining homeostasis. The mechanism(s) through which cellular cues are transmitted to the mARS remain to be investigated.

LysRS also regulates antiviral pathways, particularly in response to RNA: DNA hybrids. LysRS binds and sequesters RNA: DNA hybrids that arise as a consequence of chronic inflammation, thereby slowing recognition and subsequent activation of cGAS-STING (61). During chronic inflammation, DNA from nearly any source (tumor cells, dead cells, viruses, microorganisms) are sensed by cGAS, leading to its activation. Activated cGAS then synthesizes cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) as a secondary messenger which then binds to STING (stimulation of interferon genes). Subsequently, cGAMP-bound STING migrates from the endoplasmic reticulum to the golgi apparatus where it recruits and activates protein kinases TBK1 and IKK, the upstream initiators of the IRF3 and NFκB inflammatory pathways. LysRS inhibits these proinflammatory processes in two important ways, namely 1) through its N-terminal domain that interacts with RNA: DNA hybrids to delay recognition by cGAS, therefore impeding cGAMP production and 2) through LysRS-dependent production of diadenosine tetraphosphate (AP4A), a negative regulator of STING-dependent signaling. Through these complementary mechanisms, LysRS leads to resolution of chronic inflammation induced by nucleic acid ligands (61).

T-cells are a specialized group of lymphocytes that mature in the thymus. They are broadly classified into two groups, CD4⁺ T cells and CD8⁺ T-cells, both of which play key roles in adaptive immune responses. CD4⁺ T cells canonically play helper and regulatory roles although cytotoxic functions have also been reported (62, 63). CD4⁺ helper T cells are divided into several subsets namely Th1, Th2, Th17, and T_REG cells based on the cytokines they produce as well as their functional characteristics (64). T_H1 cells secrete IFN-γ and TNF to increase Type-1 immune responses including macrophage activation, B-cell activation, and cytotoxic T-cell responses. These have extensively been reviewed elsewhere (65–67). T_H1 cell polarization occurs following naïve CD4⁺ T-cell recognition of antigen presented by APCs secreting the cytokine IL-12. IL-12 receptor signaling in T-cells activates transcription factors including T-bet and STAT4, regulating T_H1-associated genes that mediate differentiation into the T_H1 cell phenotype (68–70). T_H2 cell polarization is mediated by APCs secreting IL-4 which mediates the upregulation of the GATA3 and STAT6 transcription factors (71). These regulate the expression of the T_H2 gene signature, which is characterized by the production of IL-4, IL-13, and IL-5. T_H2 responses are important in mediating allergy and defense against eukaryotic pathogens. T_H17 differentiation is driven by APC secretion of IL-6 and TGF-β, driving the expression of the RORγt transcription factor and production of IL-17 and IL-22 (72, 73). T regulatory cells (Tregs) act to suppress immune responses to maintain homeostasis and self-tolerance. Tregs can be categorized as “natural”, developing in the thymus during negative selection, or “induced” by tolerogenic antigen presentation in the periphery. Regulatory T cells express the Foxp3 transcription factor and are characterized by the production of the tolerogenic cytokine IL-10 (74). CD8⁺ T cells on the other hand, are generally associated with T_H1 immunity and known for their cytotoxic function (75, 76). CD8⁺ T-cells are activated by APC presentation of antigens via MHC class I in conjunction with IL-12 secretion. Activated CD8⁺ T-cells kill target cells through directed release of cytotoxic molecules including granzyme B, perforin, and IFN-γ and are critical for antitumor and antiviral immunity (77–80).

Through its subunits, the mARS complex regulates several aspects of T-cell biology including activation, differentiation, and effector functions. The mARS component AIMp1 enhances T_H1 immunity when released and secreted. Kim et al. demonstrated that mice treated with a DNA adjuvant encoding a fusion protein that linked an anti-CD3 single chain Fv to AIMp1 significantly upregulated T_H1 immune responses as characterized by increased IFN-γ production in CD4⁺ T-cells and increased levels of IgG_2a with concomitant functional inhibition of T_H2 immunity (81). Interestingly, a contrasting study suggested that in CD4⁺ T-cells, AIMp1 may drive T regulatory cell differentiation rather than T_H1 immune responses (82). Here, AIMp1 inhibited T-cell receptor (TCR)-dependent activation by reducing lipid raft association in AIMp1 treated cells. Accordingly, the reduced lipid raft association limited the formation of TCR-centered molecular activation clusters and downstream activation (82). TCR stimuli-induced calcium influx was then reduced in addition to phosphorylation of downstream signaling molecules PLCγ and PI3K when CD4⁺ T-cells were cultured in presence of AIMp1 (82). This result may have been model dependent and its physiologic relevance remains unclear. Additional work should resolve these conflicting reports.

ProRS, another subunit of the mARS complex which is present as GluProRS, is reported to mediate T_H17 differentiation. Febrifugine, a bioactive compound in many Chinese medicinal herbs mediates its tolerogenic effects by inhibiting the pro-T_H17 function of ProRS. Halofuginone (HF), a derivative of febrifugine, competes with proline for binding to the ProRS tRNA binding site, leading to the accumulation of uncharged tRNA^pro. The accumulation of tRNA^pro activates the amino acid response pathway (AAR) characterized by GCN2 autophosphorylation and induction of the AAR-response gene DIT3. DIT3 regulates cellular responses to stress including inhibition of T_H17 differentiation (83, 84). The inhibitory effects of halofuginone on ProRS can be reversed by supplementation of proline or GluProRS (83, 84). Indeed, treatment with HF has been shown to reverse T_H17-mediated multiple sclerosis in mouse models (83). Further, GluProRS also may join the GAIT complex following its release from the mARS and regulate the expression of proinflammatory genes (58). Lastly, the expression of LysRS in tumor-associated immune cells (TAIs) including macrophages/monocytes and CD4⁺ T cells correlated with longer overall survival in patients with gastric carcinomas (85). Interestingly, the expression of LysRS in tumor cells was correlated with poor prognostic parameters including larger tumor size, higher Ki-67 proliferation index, increased vascular invasion, and overall shorter survival (85). How LysRS in TAIs mediates antitumor effects remains a subject of investigation.

B cells are mediators of adaptive humoral immunity through their role as antigen-presenting cells and through the production of antibodies directed against self or non-self antigens. Mature B-cells recirculate within secondary lymphoid organs in search of their cognate antigens. Once these antigens are encountered, B cells process, internalize, and present them to helper T-cells which are critical for germinal center formation, class switching, affinity maturation, and the development of memory (86). More recently, regulatory B-cells have been described as a small subset of B cells that have immune inhibitory characteristics similar to those of T regulatory cells (87, 88). While limited data exist on the role of the mARS complex or its subunits in B-cells, Kim et al. (2015) reported AIMp1 as a novel B-cell activator via stimulation of the PKC-NFκB pathway (89). AIMp1 increases B-cell activation and proliferation as demonstrated by increased expression of activation markers including CD86, CD69, and MHC class II. AIMp1 also increased the expression of activation-induced deaminase (AID), an enzyme critical for somatic hypermutation and class switching as demonstrated by elevated levels of antigen-specific IgG₁, IgG_2a/IgG_2b, IgG₃, and IgE (89).

Microglia are tissue resident macrophages of the central nervous system and provide primary immune surveillance of the brain. Microglia respond to DAMPs or PAMPs by generating proinflammatory cytokines and presenting phagocytosed antigens. Depending on the stimuli, microglia can differentiate into pro-inflammatory M1 state or anti-inflammatory M2 state. M1 microglia secrete proinflammatory cytokines including IL-6 and TNFα and are linked to neuroinflammation and severe CNS disease. In contrast, M2 microglia are anti-inflammatory and maintain basal brain immune homeostasis (90, 91). Just as in other immune cell types, subunits of the mARS complex modulate microglial function. Such subunits include AIMp1 which promotes activation and proinflammatory functions of microglia. Kim et al. (2022) demonstrated that treatment of microglia with AIMp1 led to M1 polarization with increased production of proinflammatory cytokines including IL-6, IL-1β, and TNF. Additionally, CD86, MHC class II, and the M1 specific marker CD68 were also upregulated (92). JNK and p38 MAPK pathways were the upstream regulators of AIMp1-induced microglial cell activation, and pharmacologic inhibition of JNK and/or p38MAPK significantly reversed the M1-polarizing effects of AIMp1 (92).

Endothelial monocyte-activating polypeptide II (EMAP II), a proinflammatory cytokine generated by cleavage of the AIMp1 C-terminal domain, is highly expressed in microglia during neurodegenerative conditions including neurotoxic lesions (93) and status epilepticus (94). Similarly, ArgRS has been reported to play a role in microglial activation during ischemic stroke (95). Moderate microglial activation following stroke induces the scavenger role of clearing cellular debris whereas overactivated microglia induce production of proinflammatory molecules including cytokines, nitric oxide, and reactive oxygen species (ROS) (96, 97). This leads to recruitment of other immune cells which orchestrate nonspecific innate immune responses, significantly exacerbating ischemic injury. In a rat model of ischemic brain injury, ArgRS knockout alleviated the hyperactivated phenotype of microglia and provided neuroprotective effects by sparing mitochondrial morphological and functional integrity from ischemic insult, thus attenuating brain injury (95).

Osteoclasts are bone-resorbing cells that differentiate from the monocyte/macrophage lineage upon exposure to macrophage colony stimulating factor (M-CSF) and receptor activation of NFκB ligand RANKL (98, 99). Because of their bone-degrading functions, osteoclasts are involved in various bone pathologies including osteoporosis, bone tumors, and Paget’s disease (100). Certain subunits of the mARS complex have been shown to regulate aspects of osteoclast differentiation and function. For example, AIMp1 has been reported to be a novel oncogene in multiple myeloma, promoting osteoclastogenesis and contributing to osteoclastogenesis-induced multiple myeloma (101). Multiple myeloma is a hematological malignancy characterized by abnormal clonal plasma cells in the born marrow with potential for uncontrolled growth which may cause destructive bone lesions, kidney injury, and hypercalcemia. The interaction of myeloma cells with the bone microenvironment activates osteoclasts while suppressing osteoblasts, thereby leading to bone loss (102, 103). Wei et al. (2022) reported that AIMp1 mediates pathology in multiple myeloma by interacting with ANP32A, a histone acetyltransferase, to promote the histone acetylation enrichment function of GRB2-associated and regulator of MAPK protein 2 (GAREM2) and increase activation of the MAPK signaling pathway (101). ANP32A expression was increased in patients with MM, and increased expression was correlated with reduced survival. Further, treatment with AIMp1 activated the nuclear factor of activated T cells c1 (NFATc1) to mediate osteoclast differentiation, suggesting that several signaling pathways are involved in AIMp1-driven multiple myeloma. Indeed, AIMp1 levels were elevated at both the transcript and protein level in MM patients and were associated with decreased survival and elevated Ki-67 expression (101). Similarly, Hong et al. (2015) reported that AIMp1 induced osteoclastogenesis in vitro and was elevated in rheumatoid arthritis (RA) patients (104). As such, AIMp1 has been evaluated as a therapeutic target both in MM and RA. Wei et al. (2022) demonstrated that siAIMp1-loaded exosomes can suppresses MM and reduce osteoclast differentiation both in vitro and in vivo ( 101) while another group demonstrated that targeting AIMp1 with a monoclonal antibody atliximab inhibited AIMp1-mediated osteoclastogenesis in vitro and significantly reduced disease severity in a mouse model of collagen-induced arthritis (104). While AIMp1 presents a promising target in the treatment of several immune-related diseases, we still have open questions on how this might affect the mARS complex dynamics and cellular homeostasis. More studies are needed to address these key questions to ensure the success of AIMp1 targeting therapies in clinical development. Additionally, there is growing evidence that IleRS plays a role in osteoclast-mediated osteoporosis. The small molecule inhibitor reveromycin A (RM-A) has been shown to mediate anti-osteoporosis effects by blocking aminoacylation activity of IleRS. While signaling pathways directly affected by IleRS aminoacylation activity remain to be determined, the authors demonstrated that RM-A treatment induced osteoclast cell death and associated bone resorption (105, 106).

Mast cells are tissue resident cells which play a critical role in responding to eukaryotic pathogens through the release of proinflammatory mediators following surface crosslinking of Fcε3R1 receptors (107). An extensive literature exists on the role of the mARS complex in the regulation of mast cell function through its LysRS subunit. Following FcεR1 aggregation, the MAPK pathway is activated leading to the phosphorylation of LysRS at ser207. In the mARS complex, LysRS is a dimer that binds to the N-terminal domain of AIMp2 via its dimer interface. Because ser207 is located at the dimer interface, its phosphorylation provokes structural changes that disrupt binding of LysRS to AIMp2 and induce release from the larger complex (108). Once released, LysRS drives synthesis of diadenosine tetraphosphate (AP₄A) and binds to the transcription factor Microphthalmia-associated transcription factor c (MITF) in the MITF-Hint complex. Through this mechanism, FcεR1 aggregation leads to elevated expression of MITF-responsive genes such as mast cell protease (mMCP-6 & mMCP-5), p75 nerve growth factor, granzyme B, and tryptophan hydroxylase, all critical for mast cell development and function (23, 109). Hint is a negative regulator of MITF, and qPCR assay of MITF-controlled genes including RMCP-6, c-kit receptor tyrosine kinase, lymphocyte serine protease granzyme B, and tryptophan hydroxylase demonstrated all were elevated with mediated accumulation of AP4A after receptor crosslinking. Therefore, through the synthesis of AP4A in stimulated mast cells, LysRS regulates transcriptional activity (23). Additionally, LysRS through its induction of AP4A synthesis also regulates other transcription factors within the MITF family including USF2. USF2 is a ubiquitously expressed transcription factor in eukaryotic cells and plays critical roles in cell growth and survival. Lee et al. (2005) demonstrated that USF2, Hint, and LysRS form a multiprotein complex in mast cells and that increased AP4A induced by LysRS dissociates Hint from this complex (110). Because Hint is a negative regulator of USF2, dissociation of Hint relieves the inhibitory effect, facilitating expression of USF2-responsive genes including telomerase catalytic subunit (TERT), protein tyrosine phosphate 1 (SHP), and transforming growth factor β2 (TGF-β2). Indeed, the introduction of exogenous Ap4A enhanced the expression of these USF2-regulated genes in mast cells (110). This interaction has been exploited by HIV-1 for regulation of its own genes. USF2 is one of the transcription factors that bind the HIV-1 viral promoter in the 5’ long terminal repeat (5’ LTR) to drive expression of genes regulating HIV-1 replication and latency. Tang et al. (2023) demonstrated that ser207 phosphorylation-mediated release of LysRS from the mARS complex facilitates HIV infection by upregulating USF2 activity including transcription of viral genes that facilitate HIV replication (111). Overexpression of the AIMp2 N-terminus, a peptide that stabilizes the LysRS association with the mARS complex, inhibited HIV-1 replication along with formation of proviral DNA and other USF2-controlled genes (111).