Translation and processing of normal (PiMM) and abnormal (PiZZ) human α 1 ‐antitrypsin

Individuals who are homozygous for the protease inhibitor phenotype Z (PiZ) genetic variant of a1-antitrypsin (a,-AT) have reduced plasma concentrations of al-AT, and are susceptible to premature development of pulmonary emphysema. A subset of this population develops chronic liver disease. The reduction in plasma concentrations of a,-AT results from a selective defect in secretion as the abnormal PiZ a,-AT protein accumulates within the cell. It has recently been shown in several experimental systems that the heat shock/stress response, a response characterized by the synthesis of a family of highly evolutionarily conserved proteins during thermal or chemical stress, may also be activated by the presence of abnormal proteins within the cell. Therefore, we predicted that the heat shock/stress response would be induced in the absence of thermal or chemical stress in a1-AT-synthesizing cells of PiZZ individuals. In the following study, however, we show that net synthesis of proteins in the heat shock/stress gene family (SP90, SP70, ubiquitin) is increased only in a subset of the population, PiZZ individuals with liver disease. It is not significantly increased in PiZZ individuals with emphysema or in those without apparent tissue injury. Net synthesis of stress proteins is not increased in individuals with another variant of the a,-AT gene (PiS a,-AT) and is not increased in individuals with severe liver disease but a normal a,-AT haplotype (PiM a,-AT). These results demonstrate that the synthesis of stress proteins is increased in a subset of individuals with homozygous PiZZ al-AT deficiency, those also having liver disease.

Section: Methodsmentioning

confidence: 91%

Synthesis of stress proteins is increased in individuals with homozygous PiZZ alpha 1-antitrypsin deficiency and liver disease.

Perlmutter

Schlesinger²,

Pierce³

et al. 1989

“…However, 85% of the newly synthesized polypeptide appears to be blocked in the endoplasmic production pathway of the hepatocyte, at a stage just prior to final processing of its carbohydrate sidechains, and to its entry into the Golgi secretion system. Studies using mRNA isolated from normal (MM) and deficient (ZZ) livers showed both messages were equivalent in stability and in their translation and subsequent glycosylation in cell-free systems (32)(33)(34). Injection ofthe normal M and variant Z RNA into a surrogate cell, the toad oocyte, confirmed that there was equivalent initial synthesis of the two polypeptides but showed that, whereas all the M protein was secreted, only a fraction ofthe Z antitrypsin was secreted, most ofthe Z product being blocked within the oocyte at the final (high mannose) stage of processing (35)(36)(37)(38).…”

Section: Molecular Pathology Ofthe S and Z Variantsmentioning

confidence: 99%

alpha 1-Antitrypsin: molecular pathology, leukocytes, and tissue damage.

Carrell¹

1986

261

138

Introduction: a,-antitrypsin and the serpins The maintenance of health requires a balance between the defensive and offensive systems ofthe body. One such balance that is now just becoming understood at the molecular level is the one between the enzymes that break down protein and the antiproteases that act as their inhibitors. Of particular importance is the group of closely related enzymes, the serine proteases, which are responsible for triggering the inflammatory cascades of the plasma such as coagulation, kinin release, fibrinolysis, and complement activation. The triggering by these enzymes of the plasma cascades is controlled by an appropriately specialized group of plasma protease inhibitors, e.g., antithrombin, antiplasmin, and the first component ofcomplement (C1)' inhibitor.

“…It is a prototype of the serine protease inhibitor (serpin) supergene family which includes a number of other proteins that inactivate destructive enzymes by the formation of covalently stabilized complexes (reviewed in references 3 and 4). A severe deficiency of a1 AT, characterized by selective intracellular retention ofthe mutant protein (5)(6)(7)(8)(9), is associated with chronic liver disease and premature development of pulmonary emphysema. a, AT is synthesized in human liver cells and macrophages (9)(10)(11)(12)(13).…”

mentioning

confidence: 99%

Interferon beta 2/interleukin 6 modulates synthesis of alpha 1-antitrypsin in human mononuclear phagocytes and in human hepatoma cells.

Perlmutter

May²,

Sehgal³

1989

111