INSIGHTS | PERSPECTIVES
(MyD88), whose activation starts a signaling
cascade that ultimately activates the canonical proinflammatory transcription factor
nuclear factor kB (NF-kB). The second pathway, mediated by the adapter protein Toll/
interleukin-1 receptor domain–containing
adapter-inducing interferon (TRIF) culminates in activation of interferon regulatory
factors (IRFs), promoting an antiviral gene
expression profile. After incubation with
LPS, natural killer cells from subordinate
females had markedly increased expression
of constituents of the MyD88–NF-kB proinflammatory pathway; cells from dominant females showed the opposite.
Snyder-Mackler et al. analyzed the behavioral correlates of the immune profile. As
expected, subordinate females were harassed
the most and groomed the least. Across numerous primate species, both factors roughly
equally mediate the relationship between
rank and glucocorticoid concentrations (4).
Among subordinate females, grooming frequency was the much stronger predictor of
the rank–immune expression profile. In effect, although the misery of
harassment can be enflaming,
lacking a shoulder to cry on
afterwards is worse.
Thus, social subordination
biased individuals toward inflammation, both basally and
after an inflammatory challenge (see the photo). Importantly, chronic inflammation
carries health risks, from fetal life [exposure to maternal inflammation increases vulnerability to
metabolic disease in adulthood (5)] to old age
[chronic low-grade inflammation accelerates
many biomarkers of senescence (6, 7)].
Proinflammatory responses to social
subordination raise a seeming paradox regarding stress and health. Chronic stress
can predispose toward inflammation. Yet,
high concentrations of glucocorticoids, key
mediators of the stress response, have powerful anti-inflammatory effects (prompting
the use of synthetic glucocorticoids such as
anti-inflammatory steroids). The resolution
of this paradox will require considerable
revision in the field, with the recognition
that, in various circumstances, glucocorticoids are actually proinflammatory, on
levels ranging from enhancing migration
of inflammatory cells to injury sites, to increasing NF-kB activation (8).
The study of Snyder-Mackler et al. raises
many questions. In some ways, some so-
cially subordinate monkeys resemble hu-
mans with anxiety disorders, displaying
hypervigilance and constantly scanning the
environment for threats. For example, if you
have a desirable food, eating is repeatedly
disrupted as you look to see who may be
coming to appropriate it from you. Other
subordinate animals more closely resemble
humans with major depression, displaying
the learned helplessness of not even both-
ering to eat, because you expect that los-
ing your food is inevitable. These differing
states produce different neuroendocrine
profiles (9, 10). Will they produce differing
immunologic and inflammatory profiles of
subordination as well?
Nonhuman primates display stable differ-
ences in temperament and personality (e.g.,
in response to novelty, or extent of social
engagement). There are marked neuroen-
docrine differences among nonhuman pri-
mates of the same rank but with differing
personalities (11, 12). It will be interesting
to see if personality modulates the link be-
tween social rank and inflammatory state.
Humans belong to many hierarchies that
can shift in importance in a context-depen-
dent manner (think of a mail-room clerk
acquiring prestige as captain of the com-
pany softball team). In addition, humans
have invented the primate
world’s most corrosive form
nomic status. Low socio-
economic status adversely
affects nearly every realm of
health, from increased risk
of psychiatric disorders to
accelerated telomere aging.
Surprisingly little of the so-
link arises from differential
access to health care, or exposure to risk fac-
tors. Instead, much of it is mediated by the
psychological stress of low socioeconomic
status (13). In considering how such stress
translates into pathophysiology, experts
discuss how low socioeconomic status gets
“under the skin.” The present study suggests
one important potential route. j
1. D. G. Lindburg, Ed., The Macaques: Studies in Ecology,
Behavior and Evolution (Van Nostrand Reinhold, 1980).
2. R. Sapolsky, Science 308, 648 (2005).
3. N. Snyder-Mackler et al., Science 354, 1041 (2016).
4. D. Abbott etal. , Horm.Behav. 43, 67 (2003).
5 C. Ingvorsen et al ., Acta Physiol. (Oxf.) 214, 440 (2015).
6. C. Franceschi, J. Campisi, J.Gerontol.ABiol.Sci.Med.Sci.
69, S4 (2014).
7. D. Calcada et al ., Mech. Ageing Dev.136, 138 (2014).
8. S. Sorrells, R. Sapolsky, Brain Behav. Immun.21, 259
9. I.Neumann et al., Prog. Neuropsychopharmacol. Biol.
Psychiatry 35, 1357 (2011).
10. P. Gold, Mol. Psychiatry 20, 32 (2015).
11. R.Sapolsky,J.Ray, Am. J. Primatol. 18,1(1989).
12. A. Clarke, S. Boinski, Am.J.Primatol. 37, 103 (1995).
13. M. Marmot, The Status Syndrome: How Social Standing
Affects Our Health and Longevity (Owl Books, 2005).
By Beth Levine
In 1963, the term autophagy was coined by Christian de Duve (Nobel Laureate, 1974) to denote the degradation of cellu- lar self-constituents by the lysosome (1). In 2016, the Nobel Prize in Physiology or Medicine was awarded to Yoshinori
Ohsumi for “his discoveries of mechanisms
for autophagy” (2). Such discoveries led to
the unveiling of autophagy as an evolutionarily conserved pathway that functions in
differentiation and development, physiology, and protection against aging and many
diseases (3). On page 1036 of this issue, Tsuboyama et al. (4) uncover a surprising twist
to the mechanism in mammalian cells for
forming the autophagosomal membrane,
the structure that engulfs unwanted cellular cargo for delivery to the lysosome. These
findings have implications for understanding
the various roles of autophagy-related genes
(ATGs) in membrane-trafficking and mammalian health and disease.
One of the key mechanisms of autophagy
originally described by Mizushima, Ichimura,
Ohsumi, and other colleagues was the action
of two ubiquitin-like protein conjugation systems, the ATG12 and the ATG8 (yeast)/light
chain 3 (LC3) (mammals) systems, which
function in the formation of autophagosome
membranes (5, 6). The ubiquitin-like ATG12
protein is covalently conjugated to ATG5,
whereas ATG8/LC3 is covalently conjugated
to the membrane phospholipid phosphatidylethanolamine. These reactions are catalyzed
by the common E1-like protein ATG7 and
specific E2-like proteins ATG10 and ATG3.
The prevailing paradigm has assumed that
the ATG conjugation system proteins are essential for both autophagosomal membrane
expansion and completion (see the image).
This paradigm has framed our understanding of the molecular mechanisms of autoph-
Center for Autophagy Research, Department of Internal
Medicine, Department of Microbiology, and Howard Hughes
Medical Institute, University of Texas Southwestern Medical
Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9113,
USA. Email: firstname.lastname@example.org
“Do the trials,
The ATG conjugation
states of rhesus
system is not essential for