This page explains how impaired signal termination — rather than excessive immune activation — can lock the system into persistent illness, and why the same upstream failure produces different SMPDL3B phenotypes.
Why interferon signaling can fail to terminate — and how that locks in downstream metabolic + membrane instability.
Page thesis: IFN signaling should be pulsed; phosphatase brake erosion turns pulses into overlap, creating “lock-in” without requiring persistent infection.
One look: left panel shows normal IFN pulse termination; right panel shows slowed STAT de-phosphorylation, overlapping pulses, and a baseline that never resets.
Figure P1aw — Pulse vs lock-in: phosphatase control of interferon signaling duration. Schematic comparison of normal, pulsed interferon (IFN) signaling versus a persistence-enabled “lock-in” state arising from impaired phosphatase-mediated signal termination. Left panel: Under intact control conditions, IFN stimulation produces discrete pulses of STAT phosphorylation (pSTAT) that are rapidly terminated by phosphatases through fast, post-translational de-phosphorylation. This allows antiviral gene expression to resolve fully between stimuli, preserving baseline reset and recovery capacity. Right panel: When phosphatase activity is slowed or partially impaired, STAT de-phosphorylation is delayed, extending the tail of each activation pulse. Repeated stimuli then overlap in time, preventing full return to baseline and producing a stable, elevated antiviral signaling state despite the absence of persistent infection. This persistence-enabled state represents a control-layer failure in signal termination rather than continued pathogen presence. Within the GLA framework, such IFN lock-in permits sustained downstream execution programs—including IRG1/itaconate engagement and phenotype-specific SMPDL3B consequences—by maintaining immune tone above reset thresholds. The figure illustrates how a normally adaptive pulsed response can transition into a maladaptive attractor when termination kinetics are eroded.
This diagram summarizes a core GLA principle: in ME/CFS, persistent illness can arise from failure of signal termination rather than excessive immune activation. The key defect is erosion of the phosphatase “brake” that normally shuts down IFN/STAT signaling after an antiviral response.
Convergent stressors — including ER stress, oxidative/redox stress, and NAD⁺/SIRT1 depletion — slow STAT de-phosphorylation. This does not increase immune signal intensity. Instead, it lengthens signal duration, allowing normally transient pulses to overlap and persist.
The same upstream control-layer failure can then diverge into distinct system outcomes depending on SMPDL3B phenotype:
Downstream metabolic suppression, membrane instability, and vascular/autonomic strain are secondary amplifiers. They shape symptom expression and PEM severity but do not initiate persistence.
Disease phase critically modifies how this architecture presents. In earlier phases, partial recovery allows phenotypes to remain distinguishable. In severe disease with baseline erosion, both phenotypes may appear similar due to shared loss of control — not shared mechanisms.
This is a conceptual systems model intended to guide interpretation, sequencing, and risk-aware treatment logic. It is not a diagnostic tool and remains explicitly provisional.
This one-page diagram shows the full systems logic before we examine each layer in detail. It is intended as an orientation map, not a diagnostic tool.
Goal: “ON → OFF” in 20 seconds.
Minimal explainer:
Figure P1c — Antiviral ON → OFF map: phosphatase-mediated termination of interferon signaling. Simplified schematic of the canonical type I interferon signaling pathway highlighting the ON–OFF state transition. IFN binding to IFNAR activates JAK/TYK kinases, leading to phosphorylation of STAT1 and STAT2, assembly of the ISGF3 complex, and induction of interferon-stimulated genes (ISGs), constituting the antiviral ON state. Termination of signaling occurs through phosphatase-mediated de-phosphorylation of STAT proteins, dismantling ISGF3 and restoring the cell to a non-antiviral baseline (OFF). The diagram emphasizes that signal resolution is governed by fast, post-translational control rather than transcriptional feedback. Failure of this OFF-transition permits persistence of antiviral programs even after the initiating trigger has resolved.
↑ TopGoal: distinguish signal-state control vs feedback regulators.
One-line takeaway: They decide whether IFN is pulse or persistent state.
============================================ -->Why this matters: feedback can be intact while state-resetting is impaired, producing persistence without “more trigger.”
↑ TopCore mechanism: overlapping pulses.
Figure P1b — Pulse vs lock-in. Conceptual illustration of how slowed phosphatase-mediated STAT de-phosphorylation converts discrete interferon signaling pulses into overlapping activation, preventing full return to baseline and producing a stable, persistence-enabled antiviral state in the absence of ongoing infection.
↑ TopCentral framework claim: three stress domains preferentially impair phosphatase restoration and/or activity.
A defining vulnerability of the phosphatase brake is its sensitivity to cellular redox state. Many protein phosphatases responsible for terminating interferon signaling are cysteine-based enzymes whose catalytic activity depends on the reduced state of a critical active-site cysteine. Oxidative and nitrosative stress can reversibly—and with repeated exposure, progressively—impair these enzymes by oxidizing or modifying this catalytic residue. Even modest shifts in redox tone are therefore sufficient to slow STAT de-phosphorylation without requiring changes in gene expression, receptor density, or upstream ligand availability.
Within interferon signaling, this redox sensitivity has a precise control-theoretic consequence: phosphorylation becomes temporally dominant. When phosphatase activity is partially impaired, each interferon stimulus yields a larger and longer-lived pool of phosphorylated STATs. Signal amplitude need not increase; instead, signal duration expands. As a result, the decay phase of antiviral signaling is stretched, and the system becomes more vulnerable to overlap between successive activation events.
In ME/CFS-relevant contexts, redox stress is not an isolated insult but a recurring feature driven by exertional ischemia–reperfusion, mitochondrial inefficiency, inflammatory signaling, and ER oxidative protein folding. Under these conditions, phosphatase inhibition need not be complete to be biologically consequential. A modest but persistent reduction in de-phosphorylation capacity is sufficient to bias the system toward prolonged antiviral states, particularly when activation pulses recur before full baseline recovery has occurred.
Crucially, this mechanism does not require persistent infection or increased interferon production. Redox-mediated phosphatase impairment acts downstream of ligand binding and upstream of transcriptional feedback, converting normally transient interferon pulses into longer-tailed signaling events. In the GLA framework, this represents a primary control-layer defect: a failure of signal termination kinetics that permits interferon signaling to persist as a state, rather than as an ongoing response to an external trigger.
Beyond direct catalytic impairment, phosphatase brake erosion can arise from altered protein availability and signaling balance under conditions of endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) reprioritizes cellular resources toward damage containment, protein triage, and survival signaling. In doing so, it reshapes both the synthesis environment and the signaling landscape in which phosphatase-mediated termination must operate.
ER stress imposes a dual constraint on phosphatase function. First, it reduces effective phosphatase availability. Many regulatory phosphatases are short-lived, tightly regulated proteins that require proper folding, trafficking, and localization to act efficiently. Sustained ER–Golgi load, translational attenuation, and chaperone saturation can therefore slow phosphatase replenishment and turnover without eliminating expression outright. The result is not absence of the brake, but delayed or incomplete restoration following activation.
Second, ER stress biases signaling toward phosphorylation dominance. UPR activation increases stress-kinase tone and favors pathways that sustain phosphorylation states as part of an adaptive survival program. In this environment, kinase-driven signaling remains robust while de-phosphorylation capacity lags. Even if phosphatases remain catalytically competent, their relative influence is reduced because the system’s balance point has shifted toward maintaining activated states.
In interferon signaling, this imbalance has a specific consequence: STAT phosphorylation persists longer after each activation event. Signal termination becomes rate-limited not by ligand clearance or transcriptional feedback, but by the system’s reduced ability to reset signaling intermediates under sustained ER load. Importantly, this effect does not require heightened interferon input. A normal or even diminishing stimulus can produce prolonged downstream signaling when termination kinetics are slowed.
Within the GLA framework, ER stress therefore acts as a permissive condition for phosphatase brake erosion rather than a competing explanation. It does not initiate interferon signaling, but it increases the likelihood that once engaged, antiviral programs fail to fully resolve. This positions ER stress as a control-layer amplifier: by constraining signal reset and favoring phosphorylation persistence, it narrows the system’s margin for safe recovery and predisposes interferon signaling toward lock-in when combined with recurrent activation.
While redox stress and ER burden impair phosphatase function in real time, depletion of NAD⁺ compromises the system’s capacity to restore control after stress has passed. NAD⁺ is not merely a metabolic cofactor, but a central regulator of cellular recovery programs, coordinating redox buffering, mitochondrial repair, transcriptional reset, and stress resolution through NAD⁺-dependent enzymes such as sirtuins.
Reduced NAD⁺ availability weakens multiple processes required for phosphatase brake restoration. Diminished sirtuin activity impairs transcriptional and post-translational programs that support protein turnover, antioxidant capacity, and stress adaptation. As a result, oxidative damage persists longer, ER recovery is delayed, and the synthesis and stabilization of regulatory proteins—including phosphatases—become progressively less efficient. In this state, even transient insults can leave lasting control deficits.
Within interferon signaling, NAD⁺ depletion does not directly activate antiviral pathways. Instead, it degrades the system’s ability to return to baseline once activation has occurred. Phosphatase activity may recover incompletely between pulses, allowing small termination delays to accumulate across repeated activation events. Over time, this shifts the system away from a pulsed regime and toward a persistence-enabled state, even in the absence of sustained upstream stimulation.
Critically, NAD⁺ depletion links exertional stress to immune signal lock-in across time. Physical or cognitive load increases energetic demand and redox flux, accelerating NAD⁺ consumption. When recovery capacity is sufficient, NAD⁺ pools are replenished and control is restored. When recovery capacity is impaired, repeated demand erodes the baseline further, converting what should be reversible termination delays into a stable failure of reset.
In the GLA framework, NAD⁺ depletion therefore represents a meta-control failure: a loss of the biochemical infrastructure required to repair other control layers. By weakening redox buffering, prolonging ER stress, and limiting phosphatase restoration, low NAD⁺ transforms transient interferon activation into a self-reinforcing state. This completes the triad by explaining not only how the phosphatase brake is impaired, but why it fails to recover over time in susceptible systems.
Three ME/CFS-relevant stress domains converge on phosphatase-mediated STAT termination, impairing signal reset and extending antiviral state duration.
Figure P2 — Triad → brake erosion. Conceptual schematic showing how redox/ROS stress, ER stress, and NAD⁺ depletion converge to impair phosphatase activity and restoration. These stresses reduce STAT de-phosphorylation capacity, prolonging interferon signaling decay (“pSTAT tail extension”) and enabling overlap between activation pulses. This mechanism links common ME/CFS stress biology to a specific control-layer failure—signal duration control—without requiring persistent infection.
Why this matters: it links ME/CFS-relevant stress biology to a specific failure mode—duration control—without invoking a single pathogen.
↑ TopLayer discipline: phosphatase brake = control-layer duration. Itaconate/IRG1 and SMPDL3B effects = execution-layer consequences.
Why this matters: it re-centers immune termination (control) ahead of mitochondrial/metabolic effects (execution) in the integration hierarchy.
↑ TopThis is the “why this page exists” section: the same upstream IFN lock-in can diverge into different SMPDL3B phenotypes.
In the SMPDL3B-shedding phenotype, erosion of the phosphatase brake does not collapse baseline membrane anchoring. Instead, it alters control timing: interferon (IFN) signaling decays more slowly after each activation, producing a persistently primed innate state without continuous maximal activation. Phosphatase impairment lengthens STAT phosphorylation tails, elevating baseline interferon-stimulated gene (ISG) tone and narrowing the margin between quiescence and execution. The system remains capable of recovery between events, but the threshold for downstream execution is lowered.
This control-layer alteration has a specific systems consequence. Prolonged IFN tone biases innate signaling toward readiness rather than resolution. Small secondary stressors—such as exertional hypoperfusion, sleep disruption, metabolic fluctuation, or ER–Golgi load—now arrive on a background that is already partially activated. Because phosphatase-mediated signal termination is delayed, these inputs are more likely to overlap temporally with residual signaling from prior pulses. The result is not sustained inflammation, but episodic overshoot: discrete transitions into execution programs that would normally remain dormant.
Within the GLA framework, this manifests as facilitated entry into PI-PLC–mediated SMPDL3B cleavage. The execution machinery itself is not intrinsically dysregulated; rather, its activation threshold has shifted. Once triggered, PI-PLC activity produces transient loss of SMPDL3B anchoring and downstream membrane instability, followed by partial re-anchoring as signaling pressure relaxes. This yields the characteristic oscillatory pattern of the shedding phenotype: reactive flares with incomplete but meaningful recovery between episodes.
Critically, this behavior does not require persistent infection, sustained interferon production, or irreversible membrane damage. It arises from altered signal termination kinetics upstream. Phosphatase brake erosion converts a normally pulsed antiviral response into a series of broadened, overlapping activation windows. Each window increases the probability of execution without enforcing continuous engagement. In this sense, phosphatase weakness in shedding functions as a gain control problem, not a baseline attractor shift.
This distinction explains several defining clinical and experimental features of the shedding phenotype: episodic symptom flares rather than constant collapse; sensitivity to timing, sequencing, and cumulative load; and disproportionate responses to otherwise modest stressors. The same upstream IFN lock-in that produces chronic vulnerability in deficiency instead produces threshold lowering with preserved recovery bandwidth in shedding. Control is impaired, but not lost.
Why this matters: Without separating threshold lowering from baseline collapse, episodic execution can be misinterpreted as evidence of ongoing immune activation or primary membrane pathology. In the GLA model, SMPDL3B-shedding reflects a control-layer timing defect that permits repeated overshoot—not a failure of anchoring capacity itself.
In the SMPDL3B-deficient phenotype, erosion of the phosphatase brake produces a fundamentally different systems outcome. Rather than lowering execution thresholds around an otherwise recoverable baseline, prolonged interferon (IFN) signaling drives a control-state transition: the system shifts into a stable antiviral attractor from which recovery becomes progressively constrained. Here, impaired phosphatase-mediated signal termination does not merely extend activation windows—it prevents effective exit from the antiviral program altogether.
When STAT de-phosphorylation is persistently delayed, IFN signaling remains transcriptionally consequential. Interferon-stimulated gene (ISG) expression is maintained at baseline rather than resolving fully between pulses. This sustained transcriptional pressure imposes chronic ER load, reinforces oxidative stress, and accelerates NAD⁺ depletion. In the deficient architecture, these stresses directly undermine recovery programming mediated by SIRT1 and c-Myc, reducing the cell’s capacity to re-establish membrane organization and SMPDL3B expression after perturbation. Each activation event therefore produces net loss rather than oscillatory overshoot.
Within the GLA framework, this represents a collapse of recovery bandwidth. The system no longer fails episodically due to excessive execution, but continuously due to insufficient reset capacity. SMPDL3B deficiency emerges not as an acute cleavage event, but as a sustained low-anchoring baseline driven by transcriptional suppression and impaired re-anchoring. Downstream consequences—membrane fragility, endothelial instability, metabolic vulnerability—are secondary expressions of this upstream control failure, not independent drivers.
Crucially, the same phosphatase brake erosion that yields threshold lowering in shedding now enforces state persistence in deficiency. Because recovery mechanisms are compromised, even modest signaling persistence is sufficient to maintain ER stress and redox imbalance, which in turn further impair phosphatase activity. This creates a self-reinforcing loop: IFN persistence degrades recovery capacity, and degraded recovery capacity stabilizes IFN persistence. The antiviral state becomes an attractor rather than a transient response.
This distinction explains why deficient systems do not demonstrate clean inter-episode recovery, why amplification strategies tend to drain reserve rather than restore function, and why late-stage deficient disease presents as collapse-prone rather than reactive. Symptoms reflect loss of control rather than excessive execution. Importantly, this pattern does not require higher interferon levels than those seen in shedding; it arises from differences in downstream architecture once termination kinetics fail.
Why this matters: Without recognizing attractor formation and recovery bandwidth collapse, SMPDL3B-deficient disease can be misinterpreted as primary mitochondrial failure or irreversible damage. In the GLA model, deficiency reflects a control-layer lock-in that stabilizes a low-anchoring baseline. The disease burden follows from inability to exit this state—not from continuous immune attack.
Same control-layer defect (slow STAT de-phosphorylation) can diverge into distinct downstream phenotypes. Control-layer → execution-layer discipline preserved.
Figure P4 | Phenotype-specific divergence downstream of a shared interferon control-layer lock-in. A single upstream defect—erosion of phosphatase-mediated signal termination resulting in prolonged STAT phosphorylation and interferon (IFN) persistence—can give rise to distinct downstream phenotypes depending on system architecture. In the SMPDL3B-shedding phenotype, delayed signal decay produces a primed baseline that lowers execution thresholds without abolishing recovery, facilitating episodic PI-PLC–mediated SMPDL3B cleavage and oscillatory membrane instability. In contrast, in the SMPDL3B-deficient phenotype, the same persistence of IFN signaling enforces a control-state transition characterized by sustained ER stress, redox imbalance, and NAD+-dependent recovery failure, resulting in a chronic low-anchoring baseline with minimal inter-event reset capacity. The figure emphasizes that phenotype divergence reflects differences in downstream recovery bandwidth and execution sensitivity, not differences in the initiating immune signal.
↑ TopThis section is intentionally cautious and falsifiable. It lists observations that would be more consistent with termination failure (brake erosion) versus observations that would be more consistent with a requirement for ongoing pathogen replication.
Conceptual timeline showing that brake erosion risk rises as baseline threshold erodes across Phase 1 → Phase 4. This is not a claim of inevitability—only that reduced control headroom increases the probability that pulses overlap.
Figure P6 (optional) — Phase dependence strip. Conceptual depiction that as baseline threshold erodes across disease phases, the probability that interferon activation windows overlap increases, making termination failure more clinically consequential even when trigger magnitude is unchanged.
This section defines how the framework should and should not be interpreted. Its purpose is interpretive discipline, not clinical prescription.
Optional supporting material for readers who want definitions, interpretation clarifications, and a deeper view of STAT termination logic.
A recurring point of confusion in ME/CFS research is the apparent mismatch between ongoing symptoms and relatively unremarkable blood cytokine measurements. Within a termination-failure framework, this mismatch is not paradoxical—it is expected.
Interferon (IFN) signaling is primarily a cell-intrinsic, tissue-level process. Phosphatases terminate signaling inside cells by de-phosphorylating STATs and dismantling antiviral transcriptional complexes. When this termination step is impaired, cells can remain IFN-programmed even after circulating IFN has fallen back to baseline.
In this analogy, plasma cytokine levels reflect the average state of the ocean, not the ongoing dynamics within individual rivers. A failure of STAT de-phosphorylation allows antiviral transcriptional programs to persist downstream of the original trigger. No continuous interferon production is required, and no systemic cytokine elevation need be detectable.
This distinction explains how tissue compartments can remain locked in an antiviral or stress-adapted state while standard blood panels appear normal or only transiently abnormal. Termination failure converts a pulsed immune response into a locally persistent state, invisible to assays that rely on circulating markers alone.
Importantly, this does not imply that blood measurements are useless. Rather, it constrains their interpretation: absence of elevated plasma IFN does not rule out ongoing IFN-programmed tissue states when control-layer termination kinetics are impaired.
In the GLA framework, this principle is critical for avoiding false negatives. Tissue persistence under phosphatase brake erosion provides a parsimonious explanation for symptom chronicity without requiring sustained viremia, continuous cytokine secretion, or a hidden pathogen reservoir.
Blood (ocean) reflects diluted, averaged signals; tissue compartments (rivers) can remain locally IFN-programmed when termination kinetics are impaired.
Mini schematic — Ocean vs river. Circulating markers reflect an averaged “ocean” signal, while termination failure can maintain compartmental, cell-intrinsic IFN/ISG programs in “river” tissues even when plasma IFN is low.
This appendix provides a more granular view of where interferon (IFN) signal termination can fail without expanding scope beyond the core framework. The emphasis is on control points, not exhaustive pathway detail.
In healthy physiology, IFN signaling is a pulsed, reversible state. Termination depends on timely de-phosphorylation of STAT proteins and restoration of baseline transcriptional and metabolic conditions. Brake erosion alters timing, not initiation.
In this state, signal duration is constrained by phosphatase kinetics rather than by ligand clearance alone.
Importantly, this sequence does not require increased IFN production or continuous pathogen presence. Persistence emerges from altered termination kinetics.
These modes frequently interact: ER stress and NAD+ depletion worsen redox balance, while redox stress further destabilizes recovery and protein homeostasis.
The documents below provide the systems-level context used to interpret control-layer findings in this paper. They clarify scope, layer ordering, phenotype discipline, and phase dependence, helping prevent overextension of intracellular findings into system-level or phase-invariant claims.